Indole, azaindole and related heterocyclic sulfonylureido piperazine derivatives

ABSTRACT

This invention provides compounds having drug and bio-affecting properties, their pharmaceutical compositions and method of use. In particular, the invention is concerned with sulfonylureido piperazine derivatives of Formula I. These compounds possess unique antiviral activity, whether used alone or in combination with other antivirals, antiinfectives, immunomodulators or HIV entry inhibitors. More particularly, the present invention relates to the treatment of HIV and AIDS.  
                 
 
     wherein:  
     Z is  
                 
 
     Q is selected from the group consisting of:  
                 
 
     —W— is  
                 
 
     —represents a carbon-carbon bond or does not exist; and  
     A is NR 13 R 14 .

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. ProvisionalApplication Serial No. 60/390,195 filed Jun. 20, 2002.

FIELD OF THE INVENTION

[0002] This invention provides compounds having drug and bio-affectingproperties, their pharmaceutical compositions and method of use. Inparticular, the invention is concerned with new heterocyclicsulfonylureido piperazines derivatives that possess unique antiviralactivity. More particularly, the present invention relates to compoundsuseful for the treatment of HIV and AIDS.

BACKGROUND ART

[0003] HIV-1 (human immunodeficiency virus-1) infection remains a majormedical problem, with an estimated 42 million people infected worldwideat the end of 2002. The number of cases of HIV and AIDS (acquiredimmunodeficiency syndrome) has risen rapidly. In 2002, ˜5.0 million newinfections were reported, and 3.1 million people died from AIDS.Currently available drugs for the treatment of HIV include ninenucleoside reverse transcriptase (RT) inhibitors or approved single pillcombinations(zidovudine or AZT (or Retrovir®), didanosine (or Videx®),stavudine (or Zerit®), lamivudine (or 3TC or Epivir®), zalcitabine (orDDC or Hivid®), abacavir succinate (or Ziagen®), Tenofovir disoproxilfumarate salt (or Viread®), Combivir® (contains −3TC plus AZT),Trizivir® (contains abacavir, lamivudine, and zidovudine); threenon-nucleoside reverse transcriptase inhibitors: nevirapine (orViramune®), delavirdine (or Rescriptor®) and efavirenz (or Sustiva®),and seven peptidomimetic protease inhibitors or approved formulations:saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, andKaletra® (lopinavir and Ritonavir). Each of these drugs can onlytransiently restrain viral replication if used alone. However, when usedin combination, these drugs have a profound effect on viremia anddisease progression. In fact, significant reductions in death ratesamong AIDS patients have been recently documented as a consequence ofthe widespread application of combination therapy. However, despitethese impressive results, 30 to 50% of patients ultimately failcombination drug therapies. Insufficient drug potency, non-compliance,restricted tissue penetration and drug-specific limitations withincertain cell types (e.g. most nucleoside analogs cannot bephosphorylated in resting cells) may account for the incompletesuppression of sensitive viruses. Furthermore, the high replication rateand rapid turnover of HIV-1 combined with the frequent incorporation ofmutations, leads to the appearance of drug-resistant variants andtreatment failures when sub-optimal drug concentrations are present(Larder and Kemp; Gulick; Kuritzkes; Morris-Jones et al; Schinazi et al;Vacca and Condra; Flexner; Berkhout and Ren et al; (Ref. 6-14)).Therefore, novel anti-HIV agents exhibiting distinct resistancepatterns, and favorable pharmacokinetic as well as safety profiles areneeded to provide more treatment options.

[0004] Currently marketed HIV-1 drugs are dominated by either nucleosidereverse transcriptase inhibitors or peptidomimetic protease inhibitors.Non-nucleoside reverse transcriptase inhibitors (NNRTIs) have recentlygained an increasingly important role in the therapy of HIV infections(Pedersen & Pedersen, Ref 15). At least 30 different classes of NNRTIhave been described in the literature (De Clercq, Ref. 16) and severalNNRTIs have been evaluated in clinical trials. Dipyridodiazepinone(nevirapine), benzoxazinone (efavirenz) and bis(heteroaryl) piperazinederivatives (delavirdine) have been approved for clinical use. However,the major drawback to the development and application of NNRTIs is thepropensity for rapid emergence of drug resistant strains, both in tissuecell culture and in treated individuals, particularly those subject tomonotherapy. As a consequence, there is considerable interest in theidentification of NNRTIs less prone to the development of resistance(Pedersen & Pedersen, Ref 15). A recent overview of non-nucleosidereverse transcriptase inhibitors: perspectives on novel therapeuticcompounds and strategies for the treatment of HIV infection has appeared(Buckheit, reference 99). A review covering both NRTI and NNRTIs hasappeared (De clercq, reference 100). An overview of the current state ofthe HIV drugs has been published (De clercq, reference 101).

[0005] Several indole derivatives including indole-3-sulfones,piperazino indoles, pyrazino indoles, and5H-indolo[3,2-b][1,5]benzothiazepine derivatives have been reported asHIV-1 reverse transciptase inhibitors (Greenlee et al, Ref. 1; Williamset al, Ref. 2; Romero et al, Ref. 3; Font et al, Ref. 17; Romero et al,Ref. 18; Young et al, Ref. 19; Genin et al, Ref. 20; Silvestri et al,Ref. 21). Indole 2-carboxamides have also been described as inhibitorsof cell adhesion and HIV infection (Boschelli et al, U.S. Pat. No.5,424,329, Ref. 4). 3-substituted indole natural products(Semicochliodinol A and B, didemethylasterriquinone and isocochliodinol)were disclosed as inhibitors of HIV-1 protease (Fredenhagen et al, Ref.22).

[0006] Structurally related aza-indole amide derivatives have beendisclosed previously (Kato et al, Ref. 23; Levacher et al, Ref. 24;Dompe Spa, WO-09504742, Ref. 5(a); SmithKline Beecham PLC, WO-09611929,Ref. 5(b); Schering Corp., U.S. Pat. No. 05,023,265, Ref. 5(c)).However, these structures differ from those claimed herein in that theyare aza-indole mono-amide rather than unsymmetrical aza-indolepiperazine sulfonylureido derivatives, and there is no mention of theuse of these compounds for treating viral infections, particularly HIV.Indole and azaindole piperazine containing derivatives have beendisclosed in three different PCT and issued U.S. patent applications(Reference 93-95, 106) None of these applications disclosessulfonylureido piperazines compounds such as described in thisinvention.

[0007] Nothing in these references can be construed to disclose orsuggest the novel compounds of this invention and their use to inhibitHIV infection.

REFERENCES CITED

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[0112] 103. T. W. von Geldern et al. J. Med. Chem 1996, 39, 968.

[0113] 104. M. Abdaoui et al. Tetrahedron 2000, 56, 2427.

[0114] 105. W. J. Spillane et al. J. Chem. Soc., Perkin Trans. 1, 1982,3, 677.

[0115] 106. Wang, Tao; Wallace, Owen B.; Zhang, Zhongxing; Meanwell,Nicholas A.; Kadow, John F. Yin, Zhiwei. Composition and AntiviralActivity of Substituted Azaindoleoxoacetic Piperazine Derivatives. U.S.patent application Ser. No. 10/214,982 filed Aug. 7, 2002, which is acontinuation-in-part application of U.S. Ser. No. 10/038,306 filed Jan.2, 2002 (corresponding to PCT Int. Appl. (PCT/US02/00455), WO 02/062423A1, filed Jan. 2, 2002, published Aug. 15, 2002.

SUMMARY OF THE INVENTION

[0116] The present invention comprises compounds of Formula I, orpharmaceutically acceptable salts thereof, which are effective antiviralagents, particularly as inhibitors of HIV.

[0117] An embodiment of the invention are compounds of Formula I,including pharmaceutically acceptable salts thereof,

[0118] wherein:

[0119] Z is

[0120] Q is selected from the group consisting of:

[0121] —W— is

[0122] R¹, R², R³, R⁴, and R⁵, are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁸, XR⁹ and B;

[0123] R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independentlyH or (C₁₋₆)alkyl; wherein (C₁₋₆)alkyl is optionally substituted with oneto three same or different members selected from the group consisting ofhalogen, amino, OH, CN and NO₂;

[0124] m is 1 or 2;

[0125] R⁶ is O or does not exist;

[0126] R⁷ is (CH₂)_(n)R¹⁰, SO₂NH₂, SO₂NHMe or SO₂NMe₂;

[0127] n is 0-6;

[0128] R¹⁰ is selected from the group consisting of H, (C₁₋₆)alkyl,—C(O)—(C₁₋₆)alkyl, C(O)-phenyl and CONR¹¹R¹²;

[0129] R¹¹ and R¹² are each independently H, (C₁₋₆)alkyl or phenyl;

[0130] —represents a carbon-carbon bond or does not exist;

[0131] A is NR¹³R¹⁴;

[0132] R¹³ and R¹⁴ are independently selected from the group consistingof hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl, (C₁₋₆)alkoxy,(C₁₋₆)cycloalkyl, phenyl, and heteroaryl; wherein said (C₁₋₆)alkyl,phenyl and heteroaryl are independently optionally substituted with oneto three same or different halogens or from one to three same ordifferent substituents selected from F; or R¹³ and R¹⁴ taken togetherwith the nitrogen atom to which they are attached forms aheteroalicyclic ring containing 3 to 6 atoms;

[0133] heteroalicyclic is selected from the group consisting ofazetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, tetrahydrofuranyl and tetrahydropyranyl;

[0134] heteroaryl is selected from the group consisting of pyridinyl,pyrazinyl, pyridazinyl, pyrimidinyl, furanyl, thienyl, benzothienyl,thiazolyl, isothiazolyl, oxazolyl, benzooxazolyl, isoxazolyl,imidazolyl, benzoimidazolyl, 1H-imidazo[4,5-b]pyridin-2-yl,1H-imidazo[4,5-c]pyridin-2-yl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, tetrazinyl, triazinyl and triazolyl;

[0135] B is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, C(O)NR²³R²⁴, phenyl and heteroaryl; wherein said(C₁₋₆)alkyl, phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from F;

[0136] F is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl cyano, phenyl, heteroaryl, heteroalicyclic, hydroxy,(C₁₋₆)alkoxy, halogen, benzyl, —NR²⁵C(O)—(C₁₋₆)alkyl, —NR²⁶R²⁷,morpholino, nitro, —S(C₁₋₆)alkyl, -SPh, NR²⁵S(O)₂—R²⁶, piperazinyl, N-Mepiperazinyl, C(O)H, (CH2)_(n)COOR²⁸ and —CONR²⁹R³⁰; wherein said(C₁₋₆)alkyl, heteroaryl, or phenyl is optionally substituted with one tothree same or different halogens or one to three methyl groups;heteroaryl is selected from the group consisting of furanyl, thienyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; heteroalicyclic is selected from the groupconsisting of aziridinyl, azetidinyl, pyrrolidinyl, piperazinyl,N-methyl piperazinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl,azepinyl and morpholinyl;

[0137] R⁸, R⁹ and R²⁸ are independently selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl;

[0138] X is selected from the group consisting of NR³¹, O and S;

[0139] R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁹, R³⁰, R³¹ are independently selectedfrom the group consisting of hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, phenyland heteroaryl; wherein said (C₁₋₆)alkyl, phenyl, and heteroaryl areindependently optionally substituted with one to three same or differentgroup J; heteroaryl is selected from the group consisting of furanyl,thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl,pyrazinyl, pyridazinyl, and pyrimidinyl;

[0140] J is selected from the group consisting of (C₁₋₆)alkyl, hydroxy,(C₁₋₆)alkoxy, halogen, benzyl, —NR³²C(O)—(C₁₋₆)alkyl, —NR³²R³³,—S(C₁₋₆)alkyl, -SPh, (CH2)_(n)COOR²⁸ and —CONR³²R³³; wherein said(C₁₋₆)alkyl is optionally substituted with one to three same ordifferent halogens; and

[0141] R³² and R³³ are independently selected from the group consistingof hydrogen and (C₁₋₆)alkyl; wherein said (C₁₋₆)alkyl is optionallysubstituted with one to three same or different halogen, methyl, or CF₃groups.

[0142] A preferred embodiment of the invention are compounds of FormulaI, as above including pharmaceutically acceptable salts thereof,

[0143] Z is

[0144] R¹ is hydrogen;

[0145] —represents a carbon-carbon bond; and

[0146] R⁶does not exist.

[0147] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,

[0148] R⁷is hydrogen; and

[0149] R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² are each independently Hor methyl with the proviso that a maximum of one of R¹⁵-R²² is methyl.

[0150] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,

[0151] Q is a member selected from groups (A) and (B) consisting of:

[0152] provided R² and R³ are each independently hydrogen, methoxy orhalogen; and

[0153] provided R² is hydrogen, methoxy or halogen.

[0154] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,wherein

[0155] B is selected from the group consisting of —C(O)NR²³R²⁴, phenyland heteroaryl; wherein said phenyl or heteroaryl is optionallysubstituted with one to three same or different halogens or from one totwo same or different substituents selected from the group F.

[0156] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,wherein

[0157] A is selected from the group consisting of —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, -NHfuryl, -NHPh, morpholinyl, N-Me piperazinyl,—N(—CH₂—)₃, —N(—CH₂—)₄, —N(—CH₂—)₅, and pyrazolyl.

[0158] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,wherein

[0159] B is —C(O)NHMe or —C(O)NH-heteroaryl; wherein said heteroaryl isoptionally substituted with one to two substituents selected from thegroup consisting of halogen, (C₁-C₆ alkyl), amino, —NHC(O)—(C₁-C₆alkyl), -methoxy, —COOH, —CH₂COOH, —CH₂CH₂COOH, —NH(C₁-C₆ alkyl) and—N(C₁-C₆ alkyl)₂.

[0160] Another preferred embodiment of the invention are compounds ofFormula I, as above including pharmaceutically acceptable salts thereof,wherein

[0161] A is selected from the group consisting of —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, -NHfuryl, -NHPh, morpholinyl, N-Me piperazinyl,—N(—CH₂—)₃, —N(—CH₂—)₄, —N(—CH₂—)₅, and pyrazolyl; and

[0162] B is -triazolyl or pyrazolyl which is optionally substituted withone to two substituents selected from the group consisting of halogen,(C₁-C₆ alkyl), amino, —NHC(O)—(C₁-C₆ alkyl), -methoxy, —COOH, —CH₂COOH,—CH₂CH₂COOH, —NH(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂.

[0163] Another preferred embodiment of the invention are compounds ofFormula I, including pharmaceutically acceptable salts thereof, whereinthe compound is selected from Examples 1-14.

[0164] Another embodiment of the present invention is a method fortreating mammals infected with a virus, wherein said virus is optionallyHIV, comprising administering to said mammal an antiviral effectiveamount of a compound of Formula I, including pharmaceutically acceptablesalts thereof, and one or more pharmaceutically acceptable carriers,excipients or diluents; optionally the compound of Formula I can beadministered in combination with an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: (a) an AIDSantiviral agent; (b) an anti-infective agent; (c) an immunomodulator;and (d) HIV entry inhibitors.

[0165] Another embodiment of the present invention is a pharmaceuticalcomposition comprising an antiviral effective amount of a compound ofFormula I, including pharmaceutically acceptable salts thereof, and oneor more pharmaceutically acceptable carriers, excipients, diluents andoptionally in combination with an antiviral effective amount of an AIDStreatment agent selected from the group consisting of: (a) an AIDSantiviral agent; (b) an anti-infective agent; (c) an immunomodulator;and (d) HIV entry inhibitors.

DETAILED DESCRIPTION OF THE INVENTION

[0166] Since the compounds of the present invention, may possessasymmetric centers and therefore occur as mixtures of diastereomers andenantiomers, the present invention includes the individualdiastereoisomeric and enantiomeric forms of the compounds of Formula Iin addition to the mixtures thereof.

DEFINITIONS

[0167] Unless otherwise indicated, the following definitions apply.

[0168] The term “C₁₋₆ alkyl” as used herein and in the claims (unlessspecified otherwise) mean straight or branched chain alkyl groups suchas methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, amyl,hexyl and the like.

[0169] “Ph” means phenyl.

[0170] “Halogen” refers to chlorine, bromine, iodine or fluorine.

[0171] An “aryl” group refers to an all carbon monocyclic or fused-ringpolycyclic (i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, napthalenyl andanthracenyl. The aryl group may be substituted or unsubstituted. Whensubstituted the substituted group(s) is preferably one or more selectedfrom alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, heteroaryloxy, heteroalicycloxy, thiohydroxy,thioaryloxy, thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen,nitro, carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido, aminoand —NR^(x)R^(y), wherein R^(x) and R^(y) are independently selectedfrom the group consisting of hydrogen, alkyl, cycloalkyl, aryl,carbonyl, C-carboxy, sulfonyl, trihalomethyl, and, combined, a five- orsix-member heteroalicyclic ring.

[0172] As used herein, a “heteroaryl” group refers to a monocyclic orfused ring (i.e., rings which share an adjacent pair of atoms) grouphaving in the ring(s) one or more atoms selected from the groupconsisting of nitrogen, oxygen and sulfur and, in addition, having acompletely conjugated pi-electron system. Unless otherwise indicated,the heteroaryl group may be attached at either a carbon or nitrogen atomwithin the heteroaryl group. It should be noted that the term heteroarylis intended to encompass an N-oxide of the parent heteroaryl if such anN-oxide is chemically feasible as is known in the art. Examples, withoutlimitation, of heteroaryl groups are furyl, thienyl, benzothienyl,thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl,benzothiazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl,pyrrolyl, pyranyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidinyl,quinolinyl, isoquinolinyl, purinyl, carbazolyl, benzoxazolyl,benzimidazolyl, indolyl, isoindolyl, pyrazinyl, diazinyl, pyrazine,triazinyltriazine, tetrazinyl, and tetrazolyl. When substituted thesubstituted group(s) is preferably one or more selected from alkyl,cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, O-carbamyl, N-carbamyl, C-amido, N-amido, C-carboxy,O-carboxy, sulfinyl, sulfonyl, sulfonamido, trihalomethyl, ureido,amino, and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

[0173] As used herein, a “heteroalicyclic” group refers to a monocyclicor fused 3-8 membered-ring group, preferably 3-6 membered-ring group,having in the ring(s) one or more atoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Rings are selected from thosewhich provide stable arrangements of bonds and are not intended toencomplish systems which would not exist. The rings may also have one ormore double bonds. However, the rings do not have a completelyconjugated pi-electron system. Examples, without limitation, ofheteroalicyclic groups are azetidinyl, piperidyl, piperazinyl,imidazolinyl, thiazolidinyl, 3-pyrrolidin-1-yl, morpholinyl,thiomorpholinyl and tetrahydropyranyl. When substituted the substitutedgroup(s) is preferably one or more selected from alkyl, cycloalkyl,aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halogen, nitro,carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy,sulfinyl, sulfonyl, sulfonamido, trihalomethanesulfonamido,trihalomethanesulfonyl, silyl, guanyl, guanidino, ureido, phosphonyl,amino and —NR^(x)R^(y), wherein R^(x) and R^(y) are as defined above.

[0174] An “alkyl” group refers to a saturated aliphatic hydrocarbonincluding straight chain and branched chain groups. Preferably, thealkyl group has 1 to 20 carbon atoms (whenever a numerical range; e.g.,“1-20”, is stated herein, it means that the group, in this case thealkyl group may contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms,etc. up to and including 20 carbon atoms). More preferably, it is amedium size alkyl having 1 to 10 carbon atoms. Most preferably, it is alower alkyl having 1 to 4 carbon atoms. The alkyl group may besubstituted or unsubstituted. When substituted, the substituent group(s)is preferably one or more individually selected from trihaloalkyl,cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalomethanesulfonamido, trihalomethanesulfonyl, andcombined, a five- or six-member heteroalicyclic ring.

[0175] A “cycloalkyl” group refers to an all-carbon monocyclic or fusedring (i.e., rings which share and adjacent pair of carbon atoms) groupwherein one or more rings does not have a completely conjugatedpi-electron system. Examples, without limitation, of cycloalkyl groupsare cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane,cyclohexadiene, cycloheptane, cycloheptatriene and adamantane. Acycloalkyl group may be substituted or unsubstituted. When substituted,the substituent group(s) is preferably one or more individually selectedfrom alkyl, aryl, heteroaryl, heteroalicyclic, hydroxy, alkoxy, aryloxy,heteroaryloxy, heteroalicycloxy, thiohydroxy, thioalkoxy, thioaryloxy,thioheteroaryloxy, thioheteroalicycloxy, cyano, halo, nitro, carbonyl,thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl,C-amido, C-thioamido, N-amido, C-carboxy, O-carboxy, sulfinyl, sulfonyl,sulfonamido, trihalo-methanesulfonamido, trihalomethanesulfonyl, silyl,guanyl, guanidino, ureido, phosphonyl, amino and —NR^(x)R^(y) with R^(x)and R^(y) as defined above.

[0176] An “alkenyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbondouble bond.

[0177] An “alkynyl” group refers to an alkyl group, as defined herein,consisting of at least two carbon atoms and at least one carbon-carbontriple bond.

[0178] A “hydroxy” group refers to an —OH group.

[0179] An “alkoxy” group refers to both an —O-alkyl and an —O-cycloalkylgroup as defined herein.

[0180] An “aryloxy” group refers to both an —O-aryl and an —O-heteroarylgroup, as defined herein.

[0181] A “heteroaryloxy” group refers to a heteroaryl-O— group withheteroaryl as defined herein.

[0182] A “heteroalicycloxy” group refers to a heteroalicyclic-O— groupwith heteroalicyclic as defined herein.

[0183] A “thiohydroxy” group refers to an —SH group.

[0184] A “thioalkoxy” group refers to both an S-alkyl and an—S-cycloalkyl group, as defined herein.

[0185] A “thioaryloxy” group refers to both an —S-aryl and an—S-heteroaryl group, as defined herein.

[0186] A “thioheteroaryloxy” group refers to a heteroaryl-S— group withheteroaryl as defined herein.

[0187] A “thioheteroalicycloxy” group refers to a heteroalicyclic-S—group with heteroalicyclic as defined herein.

[0188] A “carbonyl” group refers to a —C(═O)—R″ group, where R″ isselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) andheteroalicyclic (bonded through a ring carbon), as each is definedherein.

[0189] An “aldehyde” group refers to a carbonyl group where R″ ishydrogen.

[0190] A “thiocarbonyl” group refers to a —C(═S)—R″ group, with R″ asdefined herein.

[0191] A “Keto” group refers to a —CC(═O)C— group wherein the carbon oneither or both sides of the C═O may be alkyl, cycloalkyl, aryl or acarbon of a heteroaryl or heteroaliacyclic group.

[0192] A “trihalomethanecarbonyl” group refers to a Z₃CC(═O)— group withsaid Z being a halogen.

[0193] A “C-carboxy” group refers to a —C(═O)O—R″ groups, with R″ asdefined herein.

[0194] An “O-carboxy” group refers to a R″C(—O)O-group, with R″ asdefined herein.

[0195] A “carboxylic acid” group refers to a C-carboxy group in which R″is hydrogen.

[0196] A “trihalomethyl” group refers to a -CZ₃, group wherein Z is ahalogen group as defined herein.

[0197] A “trihalomethanesulfonyl” group refers to an Z₃CS(═O)₂— groupswith Z as defined above.

[0198] A “trihalomethanesulfonamido” group refers to a Z₃CS(═O)₂NR^(x)—group with Z and R^(X) as defined herein.

[0199] A “sulfinyl” group refers to a —S(═O)—R″ group, with R″ asdefined herein and, in addition, as a bond only; i.e., —S(O)—.

[0200] A “sulfonyl” group refers to a —S(═O)₂R″ group with R″ as definedherein and, in addition as a bond only; i.e., —S(O)₂—.

[0201] A “S-sulfonamido” group refers to a —S(═O)₂NR^(X)R^(Y), withR^(X) and R^(Y) as defined herein.

[0202] A “N-Sulfonamido” group refers to a R″S(═O)₂NR_(X)— group withR_(x) as defined herein.

[0203] A “O-carbamyl” group refers to a —OC(═O)NR^(x)R^(y) as definedherein.

[0204] A “N-carbamyl” group refers to a R^(x)OC(═O)NR^(y) group, withR^(x) and R^(y) as defined herein.

[0205] A “O-thiocarbamyl” group refers to a —OC(═S)NR^(x)R^(y) groupwith R^(x) and R^(y) as defined herein.

[0206] A “N-thiocarbamyl” group refers to a R^(x)OC(═S)NR^(y)— groupwith R^(x) and R^(y) as defined herein.

[0207] An “amino” group refers to an —NH₂ group.

[0208] A “C-amido” group refers to a —C(═O)NR^(x)R^(y) group with R^(x)and R^(y) as defined herein.

[0209] A “C-thioamido” group refers to a —C(═S)NR^(x)R^(y) group, withR^(x) and R^(y) as defined herein.

[0210] A “N-amido” group refers to a R^(x)C(═O)NR^(y)— group, with R^(x)and R^(y) as defined herein.

[0211] An “ureido” group refers to a —NR^(x)C(═O)NR^(y)R^(y2) group withR^(x) and R^(y) as defined herein and R^(y2) defined the same as R^(x)and R^(y).

[0212] A “guanidino” group refers to a —R^(x)NC(═N)NR^(y)R^(y2) group,with R^(x), R^(y) and R^(y2) as defined herein.

[0213] A “guanyl” group refers to a R^(x)R^(y)NC(═N)— group, with R^(x)and R^(Y) as defined herein.

[0214] A “cyano” group refers to a —CN group.

[0215] A “silyl” group refers to a —Si(R″)₃, with R″ as defined herein.

[0216] A “phosphonyl” group refers to a P(═O)(OR^(x))₂ with R^(x) asdefined herein.

[0217] A “hydrazino” group refers to a —NR^(x)NR^(y)R^(y2) group withR^(x), R^(y) and R^(y2) as defined herein.

[0218] Any two adjacent R groups may combine to form an additional aryl,cycloalkyl, heteroaryl or heterocyclic ring fused to the ring initiallybearing those R groups.

[0219] It is known in the art that nitogen atoms in heteroaryl systemscan be “participating in a heteroaryl ring double bond”, and this refersto the form of double bonds in the two tautomeric structures whichcomprise five-member ring heteroaryl groups. This dictates whethernitrogens can be substituted as well understood by chemists in the art.The disclosure and claims of the present invention are based on theknown general principles of chemical bonding. It is understood that theclaims do not encompass structures known to be unstable or not able toexist based on the literature.

[0220] Physiologically acceptable salts and prodrugs of compoundsdisclosed herein are within the scope of this invention. The term“pharmaceutically acceptable salt” as used herein and in the claims isintended to include nontoxic base addition salts. Suitable salts includethose derived from organic and inorganic acids such as, withoutlimitation, hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid, methanesulfonic acid, acetic acid, tartaric acid, lacticacid, sulfinic acid, citric acid, maleic acid, fumaric acid, sorbicacid, aconitic acid, salicylic acid, phthalic acid, and the like. Theterm “pharmaceutically acceptable salt” as used herein is also intendedto include salts of acidic groups, such as a carboxylate, with suchcounterions as ammonium, alkali metal salts, particularly sodium orpotassium, alkaline earth metal salts, particularly calcium ormagnesium, and salts with suitable organic bases such as loweralkylamines (methylamine, ethylamine, cyclohexylamine, and the like) orwith substituted lower alkylamines (e.g. hydroxyl-substitutedalkylamines such as diethanolamine, triethanolamine ortris(hydroxymethyl)-aminomethane), or with bases such as piperidine ormorpholine.

[0221] In the method of the present invention, the term “antiviraleffective amount” means the total amount of each active component of themethod that is sufficient to show a meaningful patient benefit, i.e.,healing of acute conditions characterized by inhibition of the HIVinfection. When applied to an individual active ingredient, administeredalone, the term refers to that ingredient alone. When applied to acombination, the term refers to combined amounts of the activeingredients that result in the therapeutic effect, whether administeredin combination, serially or simultaneously. The terms “treat, treating,treatment” as used herein and in the claims means preventing orameliorating diseases associated with HIV infection.

[0222] The present invention is also directed to combinations of thecompounds with one or more agents useful in the treatment of AIDS. Forexample, the compounds of this invention may be effectivelyadministered, whether at periods of pre-exposure and/or post-exposure,in combination with effective amounts of the AIDS antivirals,immunomodulators, antiinfectives, or vaccines, such as those in thefollowing table. Drug Name Manufacturer Indication ANTIVIRALS 097Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reversetranscriptase (RT) inhibitor) Amprenivir Glaxo Wellcome HIV infection,141 W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) GlaxoWellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) AcemannanCarrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIVinfection, AIDS, ARC, in combination with AZT AD-439 Tanox BiosystemsHIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection, AIDS,ARC Adefovir dipivoxil Gilead Sciences HIV infection AL-721 Ethigen ARC,PGL (Los Angeles, CA) HIV positive, AIDS Alpha Interferon Glaxo WellcomeKaposi's sarcoma, HIV in combination w/Retrovir Ansamycin AdriaLaboratories ARC LM 427 (Dublin, OH) Erbamont (Stamford, CT) Antibodywhich Advanced Biotherapy AIDS, ARC Neutralizes pH Concepts Labile alphaaberrant (Rockville, MD) Interferon AR177 Aronex Pharm HIV infection,AIDS, ARC Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associatedDiseases BMS-232623 Bristol-Myers Squibb/ HIV infection, (CGP-73547)Novartis AIDS, ARC (protease inhibitor) BMS-234475 Bristol-Myers Squibb/HIV infection, (CGP-61755) Novartis AIDS, ARC (protease inhibitor)CI-1012 Warner-Lambert HIV-1 infection Cidofovir Gilead Science CMVretinitis, herpes, papillomavirus Curdlan sulfate AJI Pharma USA HIVinfection Cytomegalovirus MedImmune CMV retinitis Immune globin CytoveneSyntex Sight threatening Ganciclovir CMV peripheral CMV retinitisDelaviridine Pharmacia-Upjohn HIV infection, AIDS, ARC (RT inhibitor)Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. (Osaka,positive Japan) asymptomatic ddC Hoffman-La Roche HIV infection, AIDS,Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS,Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection,(Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz DuPont Merck HIVinfection, (DMP 266) AIDS, ARC (−)6-Chloro-4-(S)- (non-nucleoside RTcyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro-2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection(Gainesville, GA) Famciclovir Smith Kline herpes zoster, herpes simplexFTC Emory University HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) GS 840 Gilead HIV infection, AIDS, ARC (reverse transcriptaseinhibitor) HBY097 Hoechst Marion HIV infection, Roussel AIDS, ARC(non-nucleoside reverse transcriptase inhibitor) Hypericin VIMRx Pharm.HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS,Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC,asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer InstituteHIV-assoc. diseases Lamivudine, 3TC Glaxo Wellcome HIV infection, AIDS,ARC (reverse transcriptase inhibitor); also with AZT LobucavirBristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection,Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine BoeheringerHIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren NovaferonLabs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDSOctapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis,HIV Phosphonoformate Products, Inc. infection, other CMV infectionsPNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (proteaseinhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIVinfection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection,AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection,LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-MyersSquibb HIV infection, AIDS, Didehydrodeoxy- ARC Thymidine ValaciclovirGlaxo Wellcome Genital HSV & CMV infections Virazole Viratek/ICNasymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIVinfection, AIDS, ARC, with AZT Zidovudine; AZT Glaxo Wellcome HIVinfection, AIDS, ARC, Kaposi's sarcoma, in combination with othertherapies Tenofovir disoproxil, Gilead HIV infection, fumarate saltAIDS, (Viread ®) (reverse transcriptase inhibitor) Combivir ® GSK HIVinfection, AIDS, (reverse transcriptase inhibitor) abacavir succinateGSK HIV infection, (or Ziagen ®) AIDS, (reverse transcriptase inhibitor)IMMUNOMODULATORS AS-101 Wyeth-Ayerst AIDS Bropirimine Pharmacia UpjohnAdvanced AIDS Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX)CL246,738 American Cyanamid AIDS, Kaposi's Lederle Labs sarcoma EL10Elan Corp, PLC HIV infection (Gainesville, GA) FP-21399 Fuki ImmunoPharmBlocks HIV fusion with CD4+ cells Gamma Interferon Genentech ARC, incombination w/TNF (tumor necrosis factor) Granulocyte Genetics InstituteAIDS Macrophage Colony Sandoz Stimulating Factor GranulocyteHoechst-Roussel AIDS Macrophage Colony Immunex Stimulating FactorGranulocyte Schering-Plough AIDS, Macrophage Colony combinationStimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIVImmunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combinationw/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts(aldeslukin) Immune Globulin Cutter Biological Pediatric AIDS, inIntravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS,Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol Diethyl MerieuxInstitute AIDS, ARC Dithio Carbamate Alpha-2 Schering Plough Kaposi'ssarcoma Interferon w/AZT, AIDS Methionine- TNI Pharmaceutical AIDS, ARCEnkephalin (Chicago, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcomaMuramyl-Tripeptide Granulocyte Amgen AIDS, in combination ColonyStimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp.rCD4 Genentech AIDS, ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS,ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 InterferonHoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combinationw/AZT SK&F106528 Smith Kline HIV infection Soluble T4 ThymopentinImmunobiology HIV infection Research Institute (Annandale, NJ) TumorNecrosis Genentech ARC, in combination Factor; TNF w/gamma InterferonANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP PrimaquineFluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille SquibbCorp. Prevention of Nystatin Pastille oral candidiasis Ornidyl MerrellDow PCP Eflornithine Pentamidine LyphoMed PCP treatment Isethionate (IM& IV) (Rosemont, IL) Trimethoprim Antibacterial Trimethoprim/sulfaAntibacterial Piritrexim Burroughs Wellcome PCP treatment PentamidineFisons Corporation PCP prophylaxis Isethionate for Inhalation SpiramycinRhone-Poulenc Cryptosporidial diarrhea Intraconazole- Janssen-Pharm.Histoplasmosis; R51211 cryptococcal meningitis TrimetrexateWarner-Lambert PCP Daunorubicin NeXstar, Sequus Kaposi's sarcomaRecombinant Human Ortho Pharm. Corp. Severe anemia Erythropoietin assoc.with AZT therapy Recombinant Human Serono AIDS-related Growth Hormonewasting, cachexia Megestrol Acetate Bristol-Myers Squibb Treatment ofanorexia assoc. W/AIDS Testosterone Alza, Smith Kline AIDS-relatedwasting Total Enteral Norwich Eaton Diarrhea and NutritionPharmaceuticals malabsorption related to AIDS

[0223] Additionally, the compounds of the invention herein may be usedin combination with another class of agents for treating AIDS which arecalled HIV entry inhibitors. Examples of such HIV entry inhibitors arediscussed in DRUGS OF THE FUTURE 1999, 24(12), pp. 1355-1362; CELL, Vol.9, pp. 243-246, Oct. 29, 1999; and DRUG DISCOVERY TODAY, Vol. 5, No. 5,May 2000, pp. 183-194.

[0224] It will be understood that the scope of combinations of thecompounds of this invention with AIDS antivirals, immunomodulators,anti-infectives, HIV entry inhibitors or vaccines is not limited to thelist in the above Table, but includes in principle any combination withany pharmaceutical composition useful for the treatment of AIDS.

[0225] Preferred combinations are simultaneous or alternating treatmentsof with a compound of the present invention and an inhibitor of HIVprotease and/or a non-nucleoside inhibitor of HIV reverse transcriptase.An optional fourth component in the combination is a nucleosideinhibitor of HIV reverse transcriptase, such as AZT, 3TC, ddC or ddI. Apreferred inhibitor of HIV protease is indinavir, which is the sulfatesalt ofN-(2(R)-hydroxy-1-(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5-(1-(4-(3-pyridyl-methyl)-2(S)-N′-(t-butylcarboxamido)-piperazinyl))-pentaneamideethanolate, and is synthesized according to U.S. Pat. No. 5,413,999.Indinavir is generally administered at a dosage of 800 mg three times aday. Other preferred protease inhibitors are nelfinavir and ritonavir.Another preferred inhibitor of HIV protease is saquinavir which isadministered in a dosage of 600 or 1200 mg tid. Preferred non-nucleosideinhibitors of HIV reverse transcriptase include efavirenz. Thepreparation of ddC, ddI and AZT are also described in EPO 0,484,071.These combinations may have unexpected effects on limiting the spreadand degree of infection of HIV. Preferred combinations include thosewith the following (1) indinavir with efavirenz, and, optionally, AZTand/or 3TC and/or ddI and/or ddC; (2) indinavir, and any of AZT and/orddI and/or ddC and/or 3TC, in particular, indinavir and AZT and 3TC; (3)stavudine and 3TC and/or zidovudine; (4) zidovudine and lamivudine and141W94 and 1592U89; (5) zidovudine and lamivudine.

[0226] In such combinations the compound of the present invention andother active agents may be administered separately or in conjunction. Inaddition, the administration of one element may be prior to, concurrentto, or subsequent to the administration of other agent(s).

[0227] Abbreviations

[0228] The following abbreviations, most of which are conventionalabbreviations well known to those skilled in the art, are usedthroughout the description of the invention and the examples. Some ofthe abbreviations used are as follows: h = hour(s) rt = room temperaturemol = mole(s) mmol = millimole(s) g = gram(s) mg = milligram(s) mL =milliliter(s) TFA = Trifluoroacetic Acid DCE = 1,2-Dichloroethane CH₂Cl₂₌ Dichloromethane TPAP = tetrapropylammonium perruthenate THF =Tetrahydofuran DEPBT =3-(Diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)- one DMAP =4-dimethylaminopyridine P-EDC = Polymer supported1-(3-dimethylaminopropyl)-3- ethylcarbodiimide EDC =1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DMF =N,N-dimethylformamide Hunig's Base = N,N-Diisopropylethylamine mCPBA =meta-Chloroperbenzoic Acid azaindole = 1H-Pyrrolo-pyridine 4-azaindole =1H-pyrrolo[3,2-b]pyridine 5-azaindole = 1H-Pyrrolo[3,2-c]pyridine6-azaindole = 1H-pyrrolo[2,3-c]pyridine 7-azaindole =1H-Pyrrolo[2,3-b]pyridine PMB = 4-Methoxybenzyl DDQ =2,3-Dichloro-5,6-dicyano-1,4-benzoquinone OTf =Trifluoromethanesulfonoxy NMM = 4-Methylmorpholine PIP-COPh =1-Benzoylpiperazine NaHMDS = Sodium hexamethyldisilazide EDAC =1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide TMS = Trimethylsilyl DCM =Dichloromethane DCE = Dichloroethane MeOH = Methanol THF =Tetrahydrofuran EtOAc = Ethyl Acetate LDA = Lithium diisopropylamideTMP-Li = 2,2,6,6-tetramethylpiperidinyl lithium DME = DimethoxyethaneDIBALH = Diisobutylaluminum hydride HOBT = 1-hydroxybenzotriazole CBZ =Benzyloxycarbonyl PCC = Pyridinium chlorochromate

[0229] The general synthesis procedures for making the novelindoleoxoacetic sulfonylureido piperazine containing analogs of FormulaI of the invention herein are described below.

[0230] Sulfamoylation of compounds of formula Z-W—H can be achievedusing a sulfamoyl chloride (2-3 eq.) in the presence of a tertiary amine(3-10 eq.) such as triethylamine or diisopropylethylamine in ananhydrous aprotic solvent such as THF, acetonitrile or DMF attemperatures ranging from 0° C. to 25° C. to give compounds of formulaI. The reaction can be monitored by LC/MS. The sulfamoyl chlorides canbe purchased or easily prepared from sulfamic acids or amines followingliterature procedures. (See for example: T. W. von Geldern et al. J.Med. Chem 1996, 39, 968; M. Abdaoui et al. Tetrahedron 2000, 56, 2427;W. J. Spillane et al. J. Chem. Soc., Perkin Trans. 1, 1982, 3, 677).

[0231] As shown in Scheme AA, H—W—SO₂-A can be prepared using similarmethodology except that Z is replaced by a protecting group such as Boc.Removal of the protecting group under standard conditions for protectinggroup material such as aq HCL or TFA as in the case of Boc generatesH—W—SO₂-A which are ready for coupling as described in Step D below.

[0232] Procedures for making Z (as defined in formula I of thedescription of the invention) are described in the Blair, Wang, Wallace,or Wang references 93-95 and 106 respectively. The entire disclosures inU.S. Pat. No. 6,469,006 granted Oct. 22, 2002; U.S. Pat. No. 6,476,034granted Nov. 5, 2002; U.S. Pat. No. 6,573,262 granted Jun. 3, 2003(corresponding to PCT WO 02/04440, published Jan. 17, 2002); and U.S.patent application Ser. No. 10/214,982 filed Aug. 7, 2002, which is acontinuation-in-part of U.S. Ser. No. 10/038,306 filed Jan. 2, 2002(corresponding to PCT WO 02/62423 published Aug. 15, 2002) areincorporated by reference herein. Additional general procedures toconstruct substituted azaindole Q and Z of Formula I and intermediatesuseful for their synthesis are described in the following Schemes.

[0233] Step A in Schemes 1, 1a, 1b, 1c, or If depicts the synthesis ofeither an aza 5 indole or indole intermediate, 2 or 2a-2e via the wellknown Bartoli reaction in which vinyl magnesium bromide reacts with anaryl or heteroaryl nitro group, such as in 1, to form a five-memberednitrogen containing ring as shown. Some references for the abovetransformation include: Bartoli et al. a) Tetrahedron Lett. 1989, 30,2129. b) J. Chem. Soc. Perkin Trans. 1 1991, 2757. c) J. Chem. Soc.Perkin Trans. II 1991, 657. d) Synthesis (1999), 1594. In the preferredprocedure, a solution of vinyl Magnesium bromide in THF (typically 1.0Mbut from 0.25 to 3.0M) is added dropwise to a solution of the nitropyridine in THF at −78° under an inert atmosphere of either nitrogen orArgon. After addition is completed, the reaction temperature is allowedto warm to −20° and then is stirred for approximately 12 h beforequenching with 20% aq ammonium chloride solution. The reaction isextracted with ethyl acetate and then worked up in a typical mannerusing a drying agent such as anhydrous magnesium sulfate or sodiumsulfate. Products are generally purified using chromatography overSilica gel. Best results are generally achieved using freshly preparedvinyl Magnesium bromide. In some cases, vinyl Magnesium chloride may besubstituted for vinyl Magnesium bromide.

[0234] Substituted azaindoles may be prepared by methods described inthe literature or may be available from commercial sources. Thus thereare many methods for carrying out step A in the literature and thespecific examples are too numerous to even list. A review on thesynthesis of 7-azaindoles has been published (Merour et. al. reference102). Alternative syntheses of aza indoles and general methods forcarrying out step A include, but are not limited to, those described inthe following references (a-k below): a) Prokopov, A. A.; Yakhontov, L.N. Khim.-Farm. Zh. 1994, 28(7), 30-51; b) Lablache-Combier, A.Heteroaromatics. Photoinduced Electron Transfer 1988, Pt. C, 134-312; c)Saify, Zafar Said. Pak. J. Pharmacol. 1986, 2(2), 43-6; d) Bisagni, E.Jerusalem Symp. Quantum Chem. Biochem. 1972, 4, 439-45; e) Yakhontov, L.N. Usp. Khim. 1968, 37(7), 1258-87; f) Willette, R. E. Advan.Heterocycl. Chem. 1968, 9, 27-105; g) Mahadevan, I.; Rasmussen, M.Tetrahedron 1993, 49(33), 7337-52; h) Mahadevan, I.; Rasmussen, M. J.Heterocycl. Chem. 1992, 29(2), 359-67; i) Spivey, A. C.; Fekner, T.;Spey, S. E.; Adams, H. J. Org. Chem. 1999, 64(26), 9430-9443; j) Spivey,A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998, 39(48), 8919-8922;k) Advances in Heterocyclic Chemistry (Academic press) 1991, Vol. 52, pg235-236 and references therein.

[0235] R_(x)=R₂-R₄ for azaindoles or R₂-R₅ for indoles

[0236] =Q (most generic definition unless specified except for caveats

[0237] R₆ is nothing

[0238] R₂ is not depicted (in the interest of convenience) but isconsidered hydrogen. Other R₂ groups would work similarly in thesetranformations within reactivity limits of a chemist skilled in the art.

[0239] R₇ is Hydrogen

[0240] Scheme 1f depicts a shorthand method for representing theintermediates used for reactions in Schemes 1a-1c, and Schemes 2-7 andgeneric Q. It is understood, for the purposes of Scheme 1f and furtherSchemes, that 1b is used to synthesize 2b-5b, 1c provides 2c-5c and 1dprovides 2d-5d etc. The substituents R_(x) represent for azaindolesR₂-R₄ and for indoles R₂-R₅. In formulas in following schemes, one ofthe substituents may be depicted but it is understood that each formualcan represent the appropriate generic azaindoles or indole in order tokeep the application succinct.

[0241] Step B. Intermediates 3 can be prepared by reaction of indole oraza-indole, intermediate 2, with an excess of ClCOCOOMe in the presenceof AlCl₃ (aluminum chloride) (Sycheva et al, Ref. 26, Sycheva, T. V.;Rubtsov, N. M.; Sheinker, Yu. N.; Yakhontov, L. N. Some reactions of5-cyano-6-chloro-7-azaindoles and lactam-lactim tautomerism in5-cyano-6-hydroxy-7-azaindolines. Khim. Geterotsikl. Soedin., 1987,100-106). Typically an inert solvent such as CH₂Cl₂ is used but otherssuch as THF, Et₂O, DCE, dioxane, benzene, or toluene may findapplicability either alone or in mixtures. Other oxalate esters such asethyl or benzyl mono esters of oxalic acid could also suffice for eithermethod shown above. More lipophilic esters ease isolation during aqueousextractions. Phenolic or substituted phenolic (such aspentafluorophenol) esters enable direct coupling of the HW-protectinggroup, such as a Boc-piperazine, in Step D without activation. Lewisacid catalysts, such as tin tetrachloride, titanium IV chloride, andaluminum chloride are employed in Step B with aluminum chloride beingmost preferred. Alternatively, the azaindole is treated with a Grignardreagent such as MeMgI (methyl magnesium iodide), methyl magnesiumbromide or ethyl magnesium bromide and a zinc halide, such as ZnCl₂(zinc chloride) or zinc bromide, followed by the addition of an oxalylchloride mono ester, such as ClCOCOOMe (methyl chlorooxoacetate) oranother ester as above, to afford the aza-indole glyoxyl ester (Shadrinaet al, Ref. 25). Oxalic acid esters such as methyl oxalate, ethyloxalate or as above are used. Aprotic solvents such as CH₂Cl₂, Et₂O,benzene, toluene, DCE, or the like may be used alone or in combinationfor this sequence. In addition to the oxalyl chloride mono esters,oxalyl chloride itself may be reacted with the azaindole and thenfurther reacted with an appropriate amine, such as a piperazinederivative.

[0242] Step C. Hydrolysis of the methyl ester, (intermediate 3a,Scheme 1) affords a potassium salt of intermediate 4a, which is coupledwith protected piperazine derivatives, such as BOC-piperazine, as shownin Step D of Scheme 1. Some typical conditions employ methanolic orethanolic sodium hydroxide followed by careful acidification withaqueous hydrochloric acid of varying molarity but 1M HCl is preferred.The acidification is not utilized in many cases as described above forthe preferred conditions. Lithium hydroxide or potassium hydroxide couldalso be employed and varying amounts of water could be added to thealcohols. Propanols or butanols could also be used as solvents. Elevatedtemperatures up to the boiling points of the solvents may be utilized ifambient temperatures do not suffice. Alternatively, the hydrolysis maybe carried out in a non polar solvent such as CH₂Cl₂ or THF in thepresence of Triton B. Temperatures of −78° C. to the boiling point ofthe solvent may be employed but −10° C. is preferred. Other conditionsfor ester hydrolysis are listed in reference 41 and both this referenceand many of the conditions for ester hydrolysis are well known tochemists of average skill in the art.

[0243] Alternative Procedures for Step B and C:

[0244] Imidazolium Chloroaluminate:

[0245] We found that ionic liquid 1-alkyl-3-alkylimidazoliumchloroaluminate is generally useful in promoting the Friedel-Crafts typeacylation of indoles and azaindoles. The ionic liquid is generated bymixing 1-alkyl-3-alkylimidazolium chloride with aluminium chloride atroom temperature with vigorous stirring. 1:2 or 1:3 molar ratio of1-alkyl-3-alkylimidazolium chloride to aluminium chloride is preferred.One particular useful imidazolium chloroaluminate for the acylation ofazaindole with methyl or ethyl chlorooxoacetate is the1-ethyl-3-methylimidazolium chloroaluminate. The reaction is typicallyperformed at ambient temperature and the azaindoleglyoxyl ester can beisolated. More conveniently, we found that the glyoxyl ester can behydrolyzed in situ at ambient temperature on prolonged reaction time(typically overnight) to give the corresponding glyoxyl acid(intermediate 4a) for amide formation (Scheme 2).

[0246] A representative experimental procedure is as follows:1-ethyl-3-methylimidazolium chloride (2 equiv.; purchased from TCI;weighted under a stream of nitrogen) was stirred in an oven-dried roundbottom flask at r.t. under a nitrogen atmosphere, and added aluminiumchloride (6 equiv.; anhydrous powder packaged under argon in ampulespurchased from Aldrich preferred; weighted under a stream of nitrogen).The mixture was vigorously stirred to form a liquid, which was thenadded azaindole (1 equiv.) and stirred until a homogenous mixtureresulted. The reaction mixture was added dropwise ethyl or methylchlorooxoacetate (2 equiv.) and then stirred at r.t. for 16 h. Afterwhich time, the mixture was cooled in an ice-water bath and the reactionquenched by carefully adding excess water. The precipitates werefiltered, washed with water and dried under high vacuum to give theazaindoleglyoxylic acid. For some examples, 3 equivalents of1-ethyl-3-methylimidazolium chloride and chlorooxoacetate may berequired.

[0247] Related references: (1) Welton, T. Chem Rev. 1999, 99, 2071; (2)Surette, J. K. D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 2753;(3) Saleh, R. Y. WO 0015594.

[0248] Step D. The acid intermediates QC(O)C(O)OH (which can also bedepicted as Z-OH) or 4a, from step C of Scheme 1, 1a, 1b, or 1crespectively is coupled with either as shown in Scheme 1 and 1b, aprotected piperazine, for example t-butyl 1-piperazinecarboxylate(Boc-piperazine), or as shown in Scheme 1a and 1c, intermediateH—W—SO₂-A (where W corresponds to claim 1 and H is hydrogen) can becoupled with the acid using standard amide bond or peptide bond formingcoupling reagents. The combination of EDAC and triethylamine intetrahydrofuran or BOPCl and diisopropyl ethyl amine in chloroform havebeen utilized most frequently but DEPBT, or other coupling reagents suchas PyBop could be utilized. Another useful coupling condition employsHATU (L. A. Carpino et. al. J. Chem. Soc. Chem Comm. 1994, 201-203; A.Virgilio et. al. J. Am. Chem. Soc. 1994, 116, 11580-11581). A generalprocedure for using this reagent is Acid (1 eq) and H—W-Boc or H—W—SO₂-Aor HCl salt (2 eq) in DMF are stirred at rt for between 1 h and 2 days.HATU (2 eq) was added in one portion and then DMAP (3 eq). The reactionwas stirred at rt for 2 to 15 h (reaction progress monitored by standardmethods ie TLC, LC/MS). The mixture is filtered through filter paper tocollect the solid. The filtrate is concentrated and water is added. Themixture is filtered again and the solid is washed with water. The solidis conbined and washed with water. Many reagents for amide bondcouplings are known by an organic chemist skilled in the art and nearlyall of these are applicable for realizing coupled amide products. Asmentioned above, DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) andN,N-diisopropylethylamine, commonly known as Hunig's base, representsanother efficient method to form the amide bond (step D) and providecompounds of claim I. DEPBT is either purchased from Adrich or preparedaccording to the procedure of Ref. 28, Li, H.; Jiang, X.; Ye, Y. -H.;Fan, C.; Romoff, T.; Goodman, M. Organic Lett., 1999, 1, 91-93.Typically an inert solvent such as DMF or THF is used but other aproticsolvents could be used.

[0249] The amide bond construction reaction could be carried out usingthe preferred conditions described above, the EDC conditions describedbelow, other coupling conditions described in this application, oralternatively by applying the conditions or coupling reagents for amidebond construction described later in this application for constructionof substituents R₂-R₅. Some specific nonlimiting examples are given inthis application.

[0250] Alternatively, the acid could be converted to a methyl esterusing excess diazomethane in THF/ether. The methyl ester in dry THFcould be reacted with the lithium amide of intermediate H—W. The lithiumamide of H—W, Li—W is formed by reacting intermediate 1 with lithiumbistrimethylsilylamide in THF for 30 minutes in an ice water coolingbath. Sodium or potassium amides could be formed similarly and utilizedif additional reactivity is desired. Other esters such as ethyl, phenyl,or pentafluorophenyl could be utilized and would be formed usingstandard methodology.

[0251] It should be noted that in many cases reactions are depicted foronly one position of an intermediate, such as the R⁵ position, forexample. It is to be understood that such reactions could be used atother positions, such as R²-R⁴, of the various intermediates. Reactionconditions and methods given in the specific examples are broadlyapplicable to compounds with other substitution and other tranformationsin this application. Schemes 1 and 2 describe general reaction schemesfor taking appropriately substituted Q (indoles and azaindoles) andconverting them to compounds of Formula I. While these schemes are verygeneral, other permutations such as carrying a precursor or precursorsto substituents R² through R⁵ through the reaction scheme and thenconverting it to a compound of Formula I in the last step are alsocontemplated methods of this invention. Nonlimiting examples of suchstrategies follow in subsequent schemes. Procedures for couplingpiperazine amides to oxoacetyl derivatives are described in the Blair,Wang, Wallace, or Wang references 93-95 and 106 respectively. The entiredisclosures in U.S. Pat. No. 6,469,006 granted Oct. 22, 2002; U.S. Pat.No. 6,476,034 granted Nov. 5, 2002; U.S. patent application Ser. No.10/027,612 filed Dec. 19, 2001, which is a continuation-in-part of U.S.Ser. No. 09/888,686 filed Jun. 25, 2001 (corresponding to PCT WO02/04440, published Jan. 17, 2002); and U.S. patent application Ser. No.10/214,982 filed Aug. 7, 2002, which is a continuation-in-part of U.S.Ser. No. 10/038,306 filed Jan. 2, 2002 (corresponding to PCT WO 02/62423published Aug. 15, 2002) are incorporated by reference herein. Theprocedures used to couple indole or azaindole oxoacetic acids topiperazine amides in these references can be used analogously to formthe compounds of this invention except the piperazine sulfonyl ureas areused in place of the piperazine benzamides. It should be stated that theprocedures incorporated from these applications encompass thepreparation of strating materials and transformations which are usefulfor enabling the preparation of compounds of this invention.

[0252] Step E. Cleaveage of the protecting group, (intermediate 5a,scheme 1) affords piperazine 6a. Some typical conditions for the removalof BOC employ acid such as HCl or TFA in a 1:1 mixture of H₂O and othersolvent such as THF, MeOH or acetonitrile. Altenatively, the cleaveagecan be carried out with an ahydrous solution of 20% TFA in methylenechloride.

[0253] Step F. Sulfamoylation of piperazine intermediate 6a was carriedout as described in scheme A. Therefore a solution of intermediate 6a inanhydrous tetrahydrofuran was treated with a sulfamoyl chloride (2-3eq.) in the presence of triethylamine (3-10eq) at room temperature for18 h to afford sulfonylurea 7a.

[0254] The amide bond construction reactions depicted in step D ofscheme 1 could be carried out using the specialized conditions describedherein or alternatively by applying the conditions or coupling reagentsfor amide bond construction described in Wallace, reference 95. Somespecific nonlimiting examples are given in this application.

[0255] Alternatively, compounds of formula I can be prepared fromcompounds of formula 6a (presented as having general formula Z-W—H) asdepicted in scheme B.

[0256] Compounds of formula Z-W—H can be treated with tertiary aminessuch as Hunig's base or triethylamine (1 eq.-2 eq.) and sulfurylchloride (0.5 eq.) in an anhydrous aprotic solvent such as methylenechloride or THF usually at temperatures between 0° C. and 25° C.Sometimes higher temperatures may be used (25° C.-75° C.) to generatesulfamoyl chloride intermediate 8. Intermediate 8 can be converted intocompounds of formula I by reaction with primary or secondary amines (2eq.-3 eq.) in the presence of a tertiary amine (3eq.-10 eq.) such asHunig's base or triethylamine in an anhydrous aprotic solvent such asacetonitrile, methylene chloride or THF at temperatures ranging from 0°C. to 25° C., although higher reaction temperatures maybe used (25°C.-75° C.).

[0257] Additional procedures for synthesizing, modifying and attachinggroups are contained in references 93-95 or 106 as incorporated earlieror described below.

[0258] Schemes 1 and 3 provide more specific examples of thetransformation previously described in Scheme A. Intermediates 9-15 areprepared by the methodologies as described for intermediates 1a-7a inScheme 1. Scheme 4 is another embodiment of the transformationsdescribed in Schemes 1 and 3. Conversion of the phenol to the chloride(Step S, Scheme 4) may be accomplished according to the proceduresdescribed in Reimann, E.; Wichmann, P.; Hoefner, G.; Sci. Pharm. 1996,64(3), 637-646; and Katritzky, A. R.; Rachwal, S.; Smith, T. P.; Steel,P. J.; J. Heterocycl. Chem. 1995, 32(3), 979-984. Step T of Scheme 4 canbe carried out as described for Step A of Scheme 1. The bromointermediate can then be converted into alkoxy, chloro, or fluorointermediates as shown in Step U of Scheme 4. When step U is theconversion of the bromide into alkoxy derivatives, the conversion may becarried out by reacting the bromide with an excess of sodium methoxidein methanol with cuprous salts, such as copper I bromide, copper Iiodide, and copper I cyanide. The reaction may be carried out attemperatures of between ambient and 175° C. but most likely will bearound 115° C. or 100° C. The reaction may be run in a pressure vesselor sealed tube to prevent escape of volatiles such as methanol. Thepreferred conditions utilize 3 eq of sodium methoxide in methanol, CuBras the reaction catalyst (0.2 to 3 equivalents with the preferred being1 eq or less), and a reaction temperature of 115° C. The reaction iscarried out in a sealed tube or sealed reaction vessel. The conversionof the bromide into alkoxy derivatives may also be carried out accordingto procedures described in Palucki, M.; Wolfe, J. P.; Buchwald, S. L.;J. Am. Chem. Soc. 1997, 119(14), 3395-3396; Yamato, T.; Komine, M.;Nagano, Y.; Org. Prep. Proc. Int. 1997, 29(3), 300-303; Rychnovsky, S.D.; Hwang, K.; J. Org. Chem. 1994, 59(18), 5414-5418. Conversion of thebromide to the fluoro derivative (Step U, Scheme 4) may be accomplishedaccording to Antipin, I. S.; Vigalok, A. I.; Konovalov, A. I.; Zh. Org.Khim. 1991, 27(7), 1577-1577; and Uchibori, Y.; Umeno, M.; Seto, H.;Qian, Z.; Yoshioka, H.; Synlett. 1992, 4, 345-346. Conversion of thebromide to the chloro derivative (Step U, Scheme 5) may be accomplishedaccording to procedures described in Gilbert, E. J.; Van Vranken, D. L.;J. Am. Chem. Soc. 1996, 118(23), 5500-5501; Mongin, F.; Mongin, O.;Trecourt, F.; Godard, A.; Queguiner, G.; Tetrahedron Lett. 1996, 37(37),6695-6698; and O'Connor, K. J.; Burrows, C. J.; J. Org. Chem. 1991,56(3), 1344-1346. Steps V, W, X, Y and Z of Scheme 4 are carried outaccording to the procedures previously described for Steps B, C, D, Eand F of Scheme 1, respectively. The steps of Scheme 4 may be carriedout in a different order as shown in Scheme 5 and Scheme 6.

[0259] Scheme 7 shows the synthesis of 4-azaindole derivatives 2b-7b,5-azaindole derivatives 2c-7c, and 7-azaindole derivatives 2d-7d. Themethods used to synthesize 1b-5b, 1c-5c, and 1d-5d are the same methodsdescribed for the synthesis of 1a-5a as described in Scheme 1. It isunderstood, for the purposes of Scheme 7, that 1b is used to synthesize2b-5b, 1c provides 2c-5c and Id provides 2d-5d.

[0260] The compounds where there is a single carbonyl between theazaindole and group W can be prepared by the method of Kelarev, V. I.;Gasanov, S. Sh.; Karakhanov, R. A.; Polivin, Yu. N.; Kuatbekova, K. P.;Panina, M. E.; Zh. Org. Khim 1992, 28(12), 2561-2568. In this methodazaindoles are reacted with trichloroacetyl chloride in pyridine andthen subsequently with KOH in methanol to provide the 3-carbomethoxyazaindoles shown in Scheme 3 which can then be hydrolyzed to the acidand carried through sequence shown in the scheme to provide thecompounds of Formula I wherein a single carbonyl links the azaindolemoiety and group W.

[0261] An alternative method for carrying out the sequence outlined insteps B-D (shown in Scheme 9) involves treating an azaindole, such as16, obtained by procedures described in the literature or fromcommercial sources, with MeMgI and ZnCl₂, followed by the addition ofClCOCOCl (oxalyl chloride) in either THF or Et₂O to afford a mixture ofa glyoxyl chloride azaindole, 17a, and an acyl chloride azaindole, 17b.The resulting mixture of glyoxyl chloride azaindole and acyl chlorideazaindole is then coupled with mono-benzoylated piperazine derivativesunder basic conditions to afford the products of step D as a mixture ofcompounds, 18a and 18b, where either one or two carbonyl groups link theazaindole and group W. Separation via chromatographic methods which arewell known in the art provides the pure 18a and 18b. Conversion of 18aand 18b to 20a and 20b can be done following steps E and F. Thissequence is summarized in Scheme 9, below.

[0262] Step F

[0263] As shown above in Scheme 15, Step F1, substituted azaindolescontaining a chloride, bromide, iodide, triflate, or phosphonate undergocoupling reactions with a boronate (Suzuki type reactions) or a stannane(Stille type coupling) to provide substituted indoles or azaindoles.This type of coupling as mentioned previously can also be used tofunctionalize vinyl halides, triflates or phosphonates to add groups Dor A or precursors. Stannanes and boronates are prepared via standardliterature procedures or as described in the experimental section ofthis application. The substitututed indoles, azaindoles, or alkenes mayundergo metal mediated coupling to provide compounds of Formula Iwherein R₄ is aryl, heteroaryl, or heteroalicyclic for example. Theindoles or azaindole intermediates, (halogens, triflates, phosphonates)may undergo Stille-type coupling with heteroarylstannanes as shown inScheme 15 or with the corresponding vinyl reagents as described inearlier Schemes. Conditions for this reaction are well known in the artand the following are three example references a) Farina, V.; Roth, G.P. Recent advances in the Stille reaction; Adv. Met.-Org. Chem. 1996, 5,1-53. b) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stillereaction; Org. React. (N. Y.) 1997, 50, 1-652. and c) Stille, J. K.Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524. Other references forgeneral coupling conditions are also in the reference by Richard C.Larock Comprehensive Organic Transformations 2nd Ed. 1999, John Wileyand Sons New York. All of these references provide numerous conditionsat the disposal of those skilled in the art in addition to the specificexamples provided in Scheme 15 and in the specific embodiments. It canbe well recognized that an indole stannane could also couple to aheterocyclic or aryl halide or triflate to construct compounds ofFormula I. Suzuki coupling (Norio Miyaura and Akiro Suzuki Chem Rev.1995, 95, 2457.) between a triflate, bromo, or chloro azaindoleintermediate and a suitable boronate could also be employed and somespecific examples are contained in this application. Palladium catalyzedcouplings of stannanes and boronates between halo azaindole or indoleintermediates or vinyl halides or vinyl triflates or similar vinylsubstrate are also feasible and have been utilized extensively for thisinvention. Preferred procedures for coupling of a chloro or bromoazaindole or vinyl halide and a stannane employ dioxane, stoichiometricor an excess of the tin reagent (up to 5 equivalents), 0.1 to 1 eq oftetrakis triphenyl phosphine Palladium (0) in dioxane heated for 5 to 15h at 110 to 120°. Other solvents such as DMF, THF, toluene, or benzenecould be employed. Another useful procedure for coupling a halo indoleor azaindole with a suitable tributyl heteroaryl or other stannaneemploys usually a slight excess (1.1 eqs) but up to several equivalentsof the stannane, 0.1 eqs CuI, 0.1 equivalents of tetrakis triphenylphosphine palladium (O) all of which is usually dissolved in dry DMF(approximately 5 mmol of halide per 25 mL of DMF but this concentrationcan be reduced for sluggish reactions or increased if solubility is anissue). The reaction is usually heated at an elevated temperature ofabout 90° C. and the reaction is usually run in a sealed reaction vesselor sealed tube. When the reaction is completed it is usually allowed tocool, filtered through methanesulfonic acid SCX cartridges with MeOH toremove triphenyl phosphine oxide, and then purified by standardcrystallization or chromatographic methods. Examples of the utility ofthese conditions are shown in Scheme Z below.

[0264] Alternatively, the Stille type coupling between a stannane (˜1.1eqs) and a vinyl, heteroaryl, or aryl halide may proceed better using(0.05 to 0.1 eq) bvPd2(dba)3 as catalyst and tri-2-furylphosphine(˜0.25eq) as the added ligand. The reaction is usually heated in THF ordioxane at a temperature between 70 and 90° C. Preferred procedures forSuzuki coupling of a chloro azaindole and a boronate employ 1:1 DMFwater as solvent, 2 equivalents of potassium carbonate as basestoichiometric or an excess of the boron reagent (up to 5 equivalents),0.1 to 1 eq of Palladium (0) tetrakis triphenyl phosphine heated for 5to 15 h at 110 to 120°. Less water is occasionally employed. Anotheruseful condition for coupling a heteroaryl or aryl boronic acid to astoichiometric amount of vinyl halide or triflate utilizes DME assolvent (˜0.33 mmol halide per 3 mL DME), ˜4 eq of 2M sodium carbonate,and 0.05 eq Pd2dba3 heated in a sealed tube or sealed vessel at 90° C.for ˜16 h. Reaction times vary with substrate. Another useful method forcoupling involves use of coupling an aryl, heteroaryl, or vinyl zincbromide or chloride coupled with a vinyl, aryl, or heteroaryl halideusing tetrakis triphenyl phosphine palladium (O) heated in THF. Detailedexample procedures for preparing the zinc reagents from halides vialithium bromide exhange and then transmetalation and reaction conditionsare contained in the experimental section. If standard conditions failnew specialized catalysts and conditions can be employed. Discussions ondetails, conditions, and alternatives for carrying out the metalmediated couplings described above can also be found in the book“Organometallics in Organic Synthesis; A Manual; 2002, 2^(nd) Ed. M.Schlosser editor, John Wiley and Sons, West Sussex, England, ISBN 0 47198416 7.

[0265] Some references (and the references therein) describing catalystswhich are useful for coupling with aryl and heteroaryl chlorides are:

[0266] Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,122(17), 4020-4028;

[0267] Varma, R. S.; Naicker, K. P. Tetrahedron Lett. 1999, 40(3),439-442; Wallow, T. I.;

[0268] Novak, B. M. J. Org. Chem. 1994, 59(17), 5034-7; Buchwald, S.;Old, D. W.;

[0269] Wolfe, J. P.; Palucki, M.; Kamikawa, K.; Chieffi, A.; Sadighi, J.P.; Singer, R. A.;

[0270] Ahman, J PCT Int. Appl. WO 0002887 2000; Wolfe, J. P.; Buchwald,S. L. Angew. Chem., Int. Ed. 1999, 38(23), 3415; Wolfe, J. P.; Singer,R. A.; Yang, B. H.;

[0271] Buchwald, S. L. J. Am. Chem. Soc. 1999, 121(41), 9550-9561;Wolfe, J. P.;

[0272] Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38(16), 2413-2416;Bracher, F.;

[0273] Hildebrand, D.; Liebigs Ann. Chem. 1992, 12, 1315-1319; andBracher, F.;

[0274] Hildebrand, D.; Liebigs Ann. Chem. 1993, 8, 837-839.

[0275] Alternatively, the boronate or stannane may be formed on theazaindole via methods known in the art and the coupling performed in thereverse manner with aryl or heteroaryl based halogens or triflates.

[0276] Known boronate or stannane agents could be either purchased fromcommercial resources or prepared following disclosed documents.Additional examples for the preparation of tin reagents or boronatereagents are contained in the experimental section, and references 93-95and 106.

[0277] Novel stannane agents could be prepared from one of the followingroutes which should not be viewed as limiting.

[0278] Boronate reagents are prepared as described in reference 71.Reaction of lithium or Grignard reagents with trialkyl borates generatesboronates. Alternatively, Palladium catalyzed couplings of alkoxydiboron or alkyl diboron reagents with aryl or heteroaryl halides canprovide boron reagents for use in Suzuki type couplings. Some exampleconditions for coupling a halide with (MeO)BB(OMe)2 utilize PdCl2(dppf), KOAc, DMSO, at 80° C. until reaction is complete when followedby TLC or HPLC analysis.

[0279] Related examples are provided in the following experimentalsection.

[0280] Methods for direct addition of aryl or heteroaryl organometallicreagents to alpha chloro nitrogen containing heterocyles or the N-oxidesof nitrogen containing heterocycles are known and applicable to theazaindoles. Some examples are Shiotani et. Al. J. Heterocyclic Chem.1997, 34(3), 901-907; Fourmigue et. al. J. Org. Chem. 1991, 56(16),4858-4864.

[0281] As shown in Schemes 12 and 13, a mixture of halo-indole orhalo-azaindole intermediate, 1-2 equivalents of copper powder, with 1equivalent preferred for the 4-F,6-azaindole series and 2 equivalentsfor the 4-methoxy,6-azaindole series; 1-2 equivalents of potassiumcarbonate, with 1 equivalent preferred for the 4-F,6-azaindole seriesand 2 equivalents for the 4-methoxy,6-azaindole series; and a 2-30equivalents of the corresponding heterocyclic reagent, with 10equivalents preferred; was heated at 135-160° C. for 4 to 9 hours, with5 hours at 160° C. preferred for the 4-F,6-azaindole series and 7 hoursat 135° C. preferred for the 4-methoxy,6-azaindole series. The reactionmixture was cooled to room temperature and filtered through filterpaper. The filtrate was diluted with methanol and purified either bypreparative HPLC or silica gel. In many cases no chromatography isnecessary, the product can be obtained by crystallization with methanol.

[0282] Alternatively, the installation of amines or N linked heteroarylsmay be carried out by heating 1 to 40 equivalents of the appropriateamine and an equivalent of the appropriate aza indole chloride, bromideor iodide with copper bronze (from 0.1 to 10 equivalents (preferablyabout 2 equivalents) and from 1 to 10 equivalents of finely pulverizedpotassium hydroxide (preferably about 2 equivalents).

[0283] Temperatures of 120° to 200° C. may be employed with 140-160° C.generally preferred. For volatile starting materials a sealed reactormay be employed. The reaction is most commonly used when the halogenbeing displaced is at the 7-position of a 6-aza or 4-azaindole but themethod can work in the 5-azaseries or when the halogen is at a differentposition (4-7 position possible). As shown above the reaction can beemployed on azaindoles unsubstituted at position 3 or intermediateswhich contain the dicarbonyl or the intact dicarbonyl piperazinesulfonyl urea.

[0284] Chemistry

[0285] All Liquid Chromatography (LC) data were recorded on a ShimadzuLC-10AS liquid chromatograph using a SPD-10AV UV-Vis detector with MassSpectrometry (MS) data determined using a Micromass Platform for LC inelectrospray mode.

[0286] LC/MS Method (i.e., Compound Identification)

[0287] Note: column A is used unless otherwise indicated in thepreparation of intermediates or examples. Column A: YMC ODS-A S7 3.0 ×50 mm column Column B: PHX-LUNA C18 4.6 × 30 mm column Column C: XTERRAms C18 4.6 × 30 mm column Column D: YMC ODS-A C18 4.6 × 30 mm columnColumn E: YMC ODS-A C18 4.6 × 33 mm column Column F: YMC C18 S5 4.6 × 50mm column Column G: XTERRA C18 S7 3.0 × 50 mm column Gradient: 100%Solvent A/0% Solvent B to 0% Solvent A/100% Solvent R_(t) in min.Gradient time: 2 minutes Hold time 1 minute Flow rate: 5 mL/min DetectorWavelength: 220 nm Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic AcidSolvent B: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid

[0288] Compounds purified by preparative HPLC were diluted in MeOH (1.2mL) and purified using the following methods on a Shimadzu LC-10Aautomated preparative HPLC system or on a Shimadzu LC-8A automatedpreparative HPLC system with detector (SPD-10AV UV-VIS) wavelength andsolvent systems (A and B) the same as above.

[0289] Preparative HPLC Method (i.e., Compound Purification)

[0290] Purification Method: Initial gradient (40% B, 60% A) ramp tofinal gradient (100% B, 0% A) over 20 minutes, hold for 3 minutes (100%B, 0% A) Solvent A: 10% MeOH/90% H₂O/0.1% Trifluoroacetic Acid SolventB: 10% H₂O/90% MeOH/0.1% Trifluoroacetic Acid Column: YMC C18 S5 20 ×100 mm column Detector 220 nm Wavelength:

[0291] General and Example Procedures Excerpted from Analogous OxoacetylPiperazineamide Applications

[0292] The procedures described in references 93-95 and 106 areapplicable example procedures for synthesizing the compounds of formulaI in this application and the intermediates used for their synthesis.The following guidelines are illustrative but not limiting.

[0293] The general Bartoli (vinyl Magnesium bromide) methods forpreparing functionalized indoles or azaindoles dexcribed in theapplications can be utilized for preparing new indoles or azaindolesfrom the appropriate nitro aromatics or heteroaromatics for thisapplication. For example, in PCT/US02/00455 (PCT WO 02/062423), thegeneral procedure for preparing intermediate 2a (7-chloro-6-azaindole)from 2-chloro-3-nitro pyridine can be considered a general procedureillustrating conditions which can be used to prepare azaindoles for thisapplication. This should be obvious since the same class of intermdiatesare needed for both inventions. Similarly, the general procedure fromthe same application to prepare intermediate 3a, Methyl(7-chloro-6azaindol-3-yl) oxoacetate, provides experimental details forcarrying our Step B of (Schemes 1-7 in this application) Similarly, thegeneral procedure from the same application to prepare intermediate 4a(Potassium(7-chloro-6azaindol-3-yl) oxoacetate, provides an example ofthe general method for hydrolying oxoacteic esters (Step C of Schemes1-1c, 3-7). General procedures for carrying out the same steps in theindole series are provided in references 93 and 95. An example Bartolireaction preparation of a functionalized indole is given in thepreparation of intermediate 1 of PCT/US01/20300 (U.S. Pat. No.6,573,262) where the preparation of 4-fluoro-7-bromo-azaindole isdescribed from 2-fluoro-5-bromonitrobenzene. Subsequent procedures forthe preparation of intermediates 2 and 3 describe procedures for addingthe alkyl oxoacetate and then for ester hydrolysis to provide thecarboxylate salt and then the carboxylic acid after acidification. Thusthe chemistry described in the incoprorated previous applications forpreparing azaindole and indole intermediates is obviously applicablesince the desired compounds are the same.

[0294] Procedures for carrying out the coupling of the indole orazaindole oxoacetic acids to piperazine amides are described in thereferences 93-95 and 106. These can also be used as procedures forpreparing the piperazine sulfonyl ureas of this invention by taking theexperimental procedures and substituting a piperazine sulfonyl urea ormon protected piperazine in place of the piperazine amide. This ispossible because both groups have a free amine with relatively similaractivity and since the other portions of both the piperazine benzamideand the piperizine sulfonyl urea are relatively unreactive to manyconditions, they can be installed similarly. For example, thepreparation of intermediate 4 of PCT/US01/20300 and the preparation ofintermediate 5a of PCT/US02/00455 describe couplings of a piperazinebenzamide or methyl piperazine benzamide to an indole or azaindoleoxoacetic acid or carboxylate salt respectively. (The acid or salt canbe used interchangeably). These same procedures can be used directly forthe preparation of the compounds of this invention by substituting thedesired piperazine sulfonyl ureas for the piperazine amides utilized.

[0295] Preparation of intermediate 5a from PCT/US02/00455

[0296] can be used as a procedure for

[0297] Preparation of intermediate 4 from PCT/US01/20300

[0298] can be used as a procedure for

[0299] Once attached via a similar amide bond, both the piperazinebenzamides and the piperazine sulfonyl urea moieties are relativelyinert and thus reaction conditions used for functionalizing indoles orazaindoles in the presence of piperazine benzamides are useful forcarrying out the same tranformations in the presence of the piperazinesulfonyl ureas. Thus the methods and transformations described inreferences 93-95 and 106 including the experimental procedures whichdescribe methods to functionalize the indole or azaindole moiety in thepiperazine amide series are generally applicable for construction andfunctionalization of the piperazine sulfonyl ureas of this invention.These same applications describe general methods and specificpreparations for obtaining stannane and boronic acid reagents used forsynthesizing the compounds of formula I.

[0300] Preparation of Example 1 from PCT/US02/00455 TypicalBoron/palladium coupling procedure

[0301] can be used as a procedure for

[0302] or even as a procedure for

[0303] functionalized indole or azaindole

[0304] where R^(x) is as described for Scheme 7

[0305] Preparation of Example 39 from PCT/US02/00455 An example of thetypical stannane/palladium coupling procedure

[0306] can be used as a procedure for

[0307] or even as a procedure for

[0308] functionalized indole or azaindole

[0309] where R^(x) is as described for Scheme 7

[0310] Preparation of Example 20 from PCT/US01/20300 An example to showhow functionalization procedures of oxoacetyl piperazine benzamides canbe used to carry out similar tranformations in the correspondingpiperidine alkenes

[0311] can be used as a procedure for

[0312] or even as a procedure for

[0313] functionalized indole or azaindole

[0314] where R^(x) is as described for Scheme 7

[0315] Preparation of Intermediates and Examples:

[0316] All starting materials, unless otherwise indicated can bepurchased from commercial sources. Methods are given for the preparationintermediates.

EXAMPLE 1

[0317]

[0318] Preparation of intermediate 1. Intermediate 1 was preparedaccording to procedures described in Wallace, O. B. et al. PCT int.appl. WO0204440, and as described in Steps A-D below.

[0319] Step A

[0320] A mixture of 4-fluoro-7-bromoindole (600 mg, 2.8 mmol) and CuCN(1.004 g, 11.2 mmol) in DMF (4 ml) was refluxed for 16 hours. Aftercooling to room temperature, the reaction mixture was poured into asolution of ammonia in MeOH (30 ml, sat.) and the residue removed byfiltration. The filtrate was added to a mixture of water (20 ml)/ammonia(20 ml, sat. aq.) and extracted with EtOAc/Ether (1/1) until TLCanalysis showed no product in the aqueous phase. The combined organicextracts were washed with brine (2×200 ml) and water (200 ml), dried(MgSO₄); evaporation in vacuo gave 4-fluoro-7-cyanoindole as a tanyellow solid (310 mg, 69%).

[0321] Step B

[0322] To a solution of KOH (13.04 g, 0.232 mol) in 14% H₂O/EtOH (50 ml)was added 4-fluoro-7-cyanoindole (900 mg, 5.60 mmol). The resultingmixture was refluxed for 12 hours, slowly cooled to room temperature,and concentrated in vacuo to about 30 ml. The residue was acidified topH 2 with HCl (˜5.5 N aq.). The precipitate was filtered, washed withexcess of water, and dried under high vacuum to afford4-fluoro-7-carboxyindole as a white solid (100% conversion). Thematerial was used without further purification.

[0323] Step C

[0324] To a suspension of 4-fluoro-7-carboxyindole in a mixture of MeOH(18 ml)/PhH (62 ml) was added (trimethylsilyl)diazomethane (8.8 ml, 17.6mmol, 2 M in hexane). The resulting mixture was stirred at roomtemperature for 30 min., quenched with excess acetic acid and evaporatedin vacuo. The crude oily material was purified by flash chromatographyusing a gradient elution (Hexane to 10% EtOAc/Hexane) to afford4-fluoro-7-carbomethoxy indole as a white solid (1.04 g, 83% two steps).

[0325] Step D

[0326] Oxalyl chloride (1.2 eq.) was added dropwise to a solution of4-fluoro-7-carbomethoxy indole (1 eq.) prepared as described above, indry THF at 0° C. After 5 min., the cool bath was removed and thereaction was allowed to warm to rt and stirred until completiondetermined by LCMS. The mixture was then concentrated under reducedpressure to provide the crude oxo acetyl chloride. Triethylamine (8.88mmol, 1.23 mL) and 1-Boc piperazine (7.4 mmol, 1.38 g) was added to asolution of the crude 3-oxoacetyl chloride of 4-fluoro-7-carbomethoxyindole (7.4 mmol) in THF (70 mL) and the mixture was stirred at roomtemperature overnight. A saturated aqueous solution of NaHCO₃ (100 mL)was added and then the mixture was extracted with methylene chloride(3×100 mL). The combined organic extracts were dried over sodium sulfateto afford a crude containing intermediate 1. This crude intermediate 1was used without further purification in the next step. MS (ESI⁺):333(M+H)⁺.

[0327] Preparation of Intermediate 2

[0328] A mixture of intermediate 1 (1.0 g, 2.3 mmol) and 40% methylaminein water (40 mL) was heated to 70° C. in a sealed flask for 5 hr. Theresulting solution was then concentrated in rotoevaporator and dried invacuo to afford intermediate 2 (1.0 g, 99%) which was used in next stepwithout further purification. ¹H NMR (500 MHz, CDCl₃): 8.12−8.11 (m,1H); 7.44−7.39 (m, 1H); 7.00−6.94 (m, 1H); 6.38−6.29 (m, 1H); 3.72−3.47(m, 8H); 3.07−3.05 (d, 3H); 1.55 (s, 9H). MS (ESI⁺): 334 (M+H-Boc)⁺.

[0329] Preparation of Intermediate 3

[0330] Intermediate 2 (1.0 g, 2.3 mmol) was treated with hydrogenchloride (7 mL, 28 mmol, 4N in dioxane) at room temperature. Afterstirring for 16 hr, the resulting mixture was concentrated and dried invacuo to afford intermediate 3 (1.0 g, 99%) which was used in next stepwithout further purification. MS (ESI⁺): 333 (M+H)⁺.

EXAMPLE 1

[0331] A THF (1 ml) solution of intermediate 3 (50 mg, 0.14 mmol) wastreated with triethylamine (39 μl, 0.28 mmol) followed bydimethylsulfamoyl chloride (30 μl, 0.28 mmol) at room temperature. Thereaction was stirred for 16 h, then concentrated in rotoevaporator. Theresidue was dissolved in methanol and purified on preparative HPLC toafford the title compound (16 mg, 27%). ¹H NMR (500 MHz, CDCl₃): 8.09(s, 1H); 7.45−7.39 (m, 1H); 6.99−6.94 (m, 1H); 6.43−6.38 (bs, 1H); 3.83(m, 2H); 3.59 (m, 2H); 3.38 (m, 2H); 3.31−3.30 (m, 2H); 3.07−3.05 (m,3H); 2.83 (s, 6H). MS (ESI⁺): 440 (M+H)⁺.

[0332] General Procedure for Preparation of Non-Commercially AvailableSulfamoyl Chlorides

[0333] Sulfamoyl chlorides were prepared in two steps from commerciallyavailable amines following Method A or B:

[0334] Method A

[0335] The corresponding amine (3 mmol) was dissolved in anhydrousmethylene chloride (3 mL) and placed in an ice bath. Chlorosulfonic acid(1 mmol) was added and the mixture was stirred at this temperature for15 min. The ice bath was removed and the stirring was continued for 1 hat rt. The sulfamic acid precipitated as white solids which werecollected by filtration, dried under vacuum and used in the next stepwithout further purification.

[0336] The corresponding sulfamic acid from step 1 (1 mmol) wassuspended in anhydrous toluene (1 mL) and the mixture was heated at 75°C. for 2 h. The homogeneous mixture was cooled to rt. Volatiles wereremoved in vacuum and the sulfamoyl chloride was used in the next stepwithout further purification.

[0337] The following sulfamoyl chlorides were prepared following methodA: Phenylsulfamoyl choride, methylsulfamoyl chloride.

[0338] Method B

[0339] The corresponding amine (10 mmol) was dissolved in anhydrousmethylene chloride (20 mL) and treated with triethylamine (10 mmol). Themixture was placed in an ice bath and sulfonyl chloride (20 mmol) wasadded dropwise. The reaction mixture was stirred at 0° C. for 15 min.,then at rt for 1 h. A saturated aqueous solution of sodium carbonate (50mL) was used to quench the reaction, and the organics were extractedwith methylene chloride (2×50 mL), dried over sodium sulfate andconcentrated in vacuum. The sulfamoyl chloride was used without furtherpurification.

[0340] The following sulfamoyl chlorides were prepared following methodB: Morpholinosulfamoyl choride.

EXAMPLE 2

[0341]

[0342] Example 2 was prepared from intermediate 3 following the sameprocedure described in example 1 using phenylsulfamoyl choride. ¹H NMR(300 MHz, CD₃OD): 8.11 (s, 1H); 7.73−7.69 (m, 1H); 7.30−7.21 (m, 3H);7.10−7.09 (m, 1H); 7.03−6.97 (m, 1H); 3.0 (m, 2H); 3.42 (m, 2H); 3.34(m, 2H); 3.29 (m, 2H); 2.96 (s, 3H). MS (ESI⁺): 488 (M+H)⁺.

EXAMPLE 3

[0343]

[0344] Example 3 was prepared from intermediate 3 following the sameprocedure described in example 1 using morpholinosulfamoyl choride. ¹HNMR (300 MHz, CDCl₃): 8.12 (d, 1H, J=3.0 Hz); 7.44−7.40 (m, 1H);7.01−6.95 (m, 1H); 6.34 (bs, 1H); 3.84−3.81 (m, 2H); 3.74−3.71 (m, 4H);3.61−3.58 (m, 2H); 3.40−3.33 (m, 4H); 3.25−3.22 (m, 4H); 3.06 (d, 3H,J=3 Hz). MS (ESI⁺): 482 (M+H)⁺.

EXAMPLE 4

[0345]

[0346] Example 4 was prepared from intermediate 3 following the sameprocedure described in example 1 using methylsulfamoyl choride andacetonitrile as a solvent instead of methylene chloride. ¹H NMR (500MHz, CD₃OD): 8.20 (s, 1H); 7.77−7.74 (m, 1H); 7.08−7.05 (m, 1H);3.86−3.84 (m, 2H); 3.61−3.59 (m, 2H); 3.36−3.32 (m, 2H); 3.24−3.22 (m,4H); 2.99 (s, 3H); 2.68 (s, 3H). MS (ESI⁺): 426 (M+H)⁺.

EXAMPLE 5

[0347]

[0348] Intermediate 1 (80 mg, 0.18 mmol) was treated with a 20% TFA inCH₂Cl₂ solution (2 mL) at room temperature for 3 h. The reaction mixturewas rotavaped down, redissolved in acetonitrile (2 mL) and treated withtriethylamine (41 uL, 0.54 mmol) and dimethylsulfamoyl chloride (39 uL,0.36 mmol). The reaction mixture was stirred at rt for 18 h, then thevolatiles were removed in vacuo and the crude was chromatographed onsilica gel using a 5%MeOH/CH₂Cl₂ solution as eluent. The fractionscontaining the title compound were combined, concentrated and purifiedusing the preparative reverse phase HPLC to afford the title compound asa white solid (37 mg, 47%). ¹HNMR (300 MHz, CDCl₃): 1.71 (bs, 1H), 8.13(s, 1H), 7.95 (m, 1H), 7.01 (m, 1H), 3.98 (s, 3H), 3.82 (m, 2H), 3.59(m, 2H), 3.33 (m, 4H), 2.84 (s, 6H). MS (ESI⁺): 441 (M+H)⁺.

EXAMPLE 6

[0349]

[0350] Example 6 was prepared from intermediate 1 following theprocedure described in example 5 using cyclobutylsufamoyl chloride.¹H-NMR (300 MHz, CDCl₃): 10.68 (bs, 1H); 8.15−8.11 (m, 1H); 7.98−7.95(m, 1H); 7.05−6.98 (m, 1H); 4.04 (s, 3H); 4.01−3.28 (m, 12H), 2.27−2.24(m, 2H). LC/MS: (ES⁺) m/z (m+H)⁺=453. Rt=1.24 min.

EXAMPLE 7

[0351]

[0352] Example 7 was prepared from intermediate 1 following theprocedure described in example 5 using piperidinesulfamoyl chloride.¹H-NMR (300 MHz, CDCl₃): 10.68 (bs, 1H); 8.14−8.13 (m, 1H); 7.98−7.95(m, 1H); 7.04−7.00 (m, 1H); 3.99 (s, 3H); 3.88−3.21 (m, 12H), 1.62−1.55(m, 6H). LC/MS: (ES⁺) m/z (m+H)⁺=481. Rt=1.40 min.

EXAMPLE 8

[0353]

[0354] Example 8 was prepared from intermediate 1 following theprocedure described in example 5 using dimethylsulfamoyl chloride.¹H-NMR (300 MHz, CDCl₃): 10.68 (bs, 1H); 8.13−8.12 (m, 1H); 7.97−7.94(m, 1H); 7.02−6.98 (m, 1H); 3.99 (s, 3H); 3.88−3.26 (m, 12H), 1.20−1.16(m, 6H). LC/MS: (ES⁺) m/z (m+H)⁺=469. Rt=1.36 min.

EXAMPLE 9

[0355]

[0356] Example 9 was prepared from intermediate 3 following theprocedure described in example 1 using piperidinesulfamoyl chloride.¹H-NMR (500 MHz, DMSO): 12.44 (bs, 1H); 8.69−8.68 (m, 1H); 8.06−8.05 m,1H); 7.81−7.79 (m, 1H); 7.12−7.09 (m, 1H); 3.69−3.10 (m, 12H); 2.86−2.85(m,3H), 1.51−1.50 (m, 6H). LC/MS: (ES⁺) m/z (m+H)⁺=480. Rt=1.32 min.

EXAMPLE 10

[0357]

[0358] Example 10 was prepared from intermediate 3 following theprocedure described in example 1 using cyclobutylsulfamoyl chloride.¹H-NMR (500 MHz, DMSO): 12.44 (bs, 1H); 8.69−8.68 (m, 1H); 8.06−8.05 (m,1H); 7.80−7.78 (m, 1H); 7.12−7.09 (m, 1H); 3.83−3.10 (m, 12H); 2.86−2.85(m, 3H), 2.20−2.16 (m, 2H). LC/MS: (ES⁺) m/z (m+H)⁺=452. Rt=1.12 min.

EXAMPLE 11

[0359]

[0360] Example 11 was prepared from intermediate 3 following theprocedure described in example 1 using dimethylsulfamoyl chloride.¹H-NMR (500 MHz, DMSO): 12.44 (bs, 1H); 8.69−8.68 (m, 1H); 8.06−8.05 (m,1H); 7.80−7.78 (m, 1H); 7.12−7.09 (m, 1H); 3.70−3.00 (m, 12H); 2.86−2.85(m, 3H), 1.10−1.08 (m, 6H). LC/MS: (ES⁺) m/z (m+H)⁺=468. Rt=1.25 min.

EXAMPLE 12

[0361]

[0362] Preparation of Intermediate 4

[0363] Intermediate 4,4-fluoro-7-bromo-6-azaindole, was preparedaccording to the following scheme:

[0364] A) fuming HNO₃, H₂SO₄;

[0365] B) POBr₃/DMF, 110° C.;

[0366] C) vinylmagnesium bromide, THF, −78° C. ˜−20° C.

[0367] Intermediate 4 was isolated as a brownish solid. MS m/z: (M+H)⁺calcd for C₇H₅BrFN₂: 214.96; found 214.97. HPLC retention time: 1.28minutes (column G).

[0368] Preparation of Intermediate 5

[0369] To a solution of 1-ethyl-3-methyl imidazolium chloride (2.7 g,18.6 mmol) and aluminum chloride (7.5 g, 55.8 mmol) was addedintermediate 4 (2.0 g, 9.3 mmol) followed by slow addition ofethyloxalylacetate (2.1 ml, 18.6 mmol) at room temperature. The reactionwas then stirred at room temperature for 20 h, and quenched by slowaddition of ice water (20 mL). A light brown solid precipitated out andcollected by filtration and dried in air to provide of intermediate 5(2.2 g, 82%). LC/MS: (ES⁺) m/z (M+H)⁺=289. Rt=0.85 min.

[0370] Preparation of Intermediate 6

[0371] A mixture of intermediate 5 (574 mg, 2.0 mmol), 1-Boc-piperazine(1.1 g, 6.0 mmol), HOBt Hydrate (612 mg, 4.0 mmol),1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (764 mg,4.0 mmol) and N-methyl-morpholine (1.3 mL, 12 mmol) in DMF (15 mL) wasstirred for 30 h at room temperature. The reaction was quenched withwater (20 mL). The resulting mixture was extracted with ethylacetate(3×30 mL). The combined organic layer was dried over magnesium sulfate,filtered and concentrated. The residue was chromatographed to affordintermediate 6 as a white powder (667 mg, 73%). ¹H NMR (300 MHz, CDCl₃):9.34 (bs, 1H); 8.26−8.25 (m, 1H); 8.11−8.10 (m, 1H); 3.74−3.50 (m, 8H);1.57 (s, 9H). LC/MS: (ES⁺) m/z (M+H)⁺=457. Rt=1.43 min.

[0372] Preparation of Intermediate 7

[0373] Intermediate 6 (417 mg, 0.92 mmol) was treated with 4N HCl indioxane (5 mL, 20 mmol). After stirring for 15 h, the reaction mixturewas concentrated on rotoevaporator and dried in vacuo. The resultinglight yellow powder was characterized by LCMS and carried to the nextstep without purification. LC/MS: (ES⁺) m/z (M+H)⁺=357. Rt=0.55 min.

[0374] Preparation of Intermediate 8

[0375] Intermediate 7 (103 mg, 0.26 mmol) was dissolved indichloromethane (1.5 mL) and treated with dimethylsufamoyl chloride (56ul, 0.52 mmol) followed by triethylamine (100 ul, 0.78 mmol). Thereaction was stirred for 15 h at room temperature. The solid wasfiltered out. The filtrate was concentrated and dried in vacuo toprovide intermediate 8 as a yellow solid which was used in the next stepwithout further purification. ¹H-NMR (300 MHz, CDCl3): 9.25 (bs, 1H);8.26−8.25 (m, 1H); 8.12−8.11 (m, 1H); 3.84−3.31 (m, 8H); 2.85 (s, 6H).LC/MS: (ES⁺) m/z (m+H)⁺=464. Rt=1.06 min.

[0376] Preparation of Compound Example 12

[0377] A mixture of intermediate 8 (53 mg, 0.12 mmol), 1,2,4-triazole(248 mg, 3.5 mmol), copper powder (8 mg, 0.12 mmol) and potassiumcarbonate (17 mg, 0.12 mmol) was heated at 160° C. for 7 h in a sealedtube. The reaction was cooled to room temperature and filtered throughfilter paper. The filtrate was diluted with methanol and purified bypreparative HPLC to provide the title compound (5.1 mg, 10%). ¹H-NMR(500 MHz, CDCl₃): 11.09 (bs, 1H); 9.30 (s, 1H); 8.32−8.31 (m, 1H); 8.24(s, 1H); 8.11−8.10 (m, 1H); 3.85−3.33(m, 8H); 2.85 (s, 6H). LC/MS: (ES⁺)m/z (m+H)⁺=451. Rt=1.12 min.

EXAMPLE 13 AND 14

[0378]

[0379] Examples 13 and 14 were prepared from intermediate 9 as describedin example 3. (The synthesis of intermediate 9 is described in Wang, T.et al., PCT WO0162255). Example 13: ¹H-NMR (300 MHz, CDCl₃): 8.33−8.30(m, 1H); 8.15−8.12 (m, 1H); 7.00−6.97 (m, 1H); 4.23 (s, 3H); 4.22−2.83(m, 7H), 2.84 (s, 6H); 1.42−1.40 (m, 3H). LC/MS: (ES⁺) m/z (m+H)⁺=410.Rt=0.87 min; Example 14: ¹H-NMR (300 MHz, CDCl₃): 8.38−8.36 (m, 1H);8.28−8.23 (m, 1H); 6.81−6.79 (m, 1H); 4.02 (s, 3H); 3.90−2.85 (m, 7H),3.07 (s, 6H); 2.85 (s, 6H); 1.42−1.40 (m, 3). LC/MS: (ES⁺) m/z(m+H)⁺=517. Rt=1.30 min.

[0380] Biology

[0381] “μM” means micromolar;

[0382] “mL” means milliliter;

[0383] “μl” means microliter;

[0384] “mg” means milligram;

[0385] The materials and experimental procedures used to obtain theresults reported in Tables 1-2 are described below.

[0386] Cells:

[0387] Virus production—Human embryonic Kidney cell line, 293T, waspropagated in Dulbecco's Modified Eagle Medium (Invitrogen, Carlsbad,Calif.) containing 10% fetal Bovine serum (FBS, Sigma, St. Louis, Mo.).

[0388] Virus infection—Human epithelial cell line, HeLa, expressing theHIV-1 receptor CD4 was propagated in Dulbecco's Modified Eagle Medium(Invitrogen, Carlsbad, Calif.) containing 10% fetal Bovine serum (FBS,Sigma, St. Louis, Mo.) and supplemented with 0.2 mg/mL Geneticin(Invitrogen, Carlsbad, Calif.).

[0389] Virus—Single-round infectious reporter virus was produced byco-transfecting human embryonic Kidney 293 cells with an HIV-1 envelopeDNA expression vector and a proviral cDNA containing an envelopedeletion mutation and the luciferase reporter gene inserted in place ofHIV-1 nef sequences (Chen et al, Ref. 41). Transfections were performedusing lipofectAMINE PLUS reagent as described by the manufacturer(Invitrogen, Carlsbad, Calif.).

[0390] Experiment

[0391] 1. HeLa CD4 cells were plated in 96 well plates at a cell densityof 1×10⁴ cells per well in 100 μl Dulbecco's Modified Eagle Mediumcontaining 10% fetal Bovine serum and incubated overnight.

[0392] 2. Compound was added in a 2 μl dimethylsulfoxide solution, sothat the final assay concentration would be ≦10 μM.

[0393] 3. 100 μl of single-round infectious reporter virus in Dulbecco'sModified Eagle Medium was then added to the plated cells and compound atan approximate multiplicity of infection (MOI) of 0.01, resulting in afinal volume of 200 μl per well.

[0394] 4. Virally-infected cells were incubated at 37 degrees Celsius,in a CO₂ incubator, and harvested 72 h after infection.

[0395] 5. Viral infection was monitored by measuring luciferaseexpression from viral DNA in the infected cells using a luciferasereporter gene assay kit, as described by the manufacturer (RocheMolecular Biochemicals, Indianapolis, Ind.). Infected cell supernatantswere removed and 50 μl of lysis buffer was added per well. After 15minutes, 50 μl of freshly-reconstituted luciferase assay reagent wasadded per well. Luciferase activity was then quantified by measuringluminescence using a Wallac microbeta scintillation counter.

[0396] 6. The percent inhibition for each compound was calculated byquantifying the level of luciferase expression in cells infected in thepresence of each compound as a percentage of that observed for cellsinfected in the absence of compound and subtracting such a determinedvalue from 100.

[0397] 7. An EC₅₀ provides a method for comparing the antiviral potencyof the compounds of this invention. The effective concentration forfifty percent inhibition (EC₅₀) was calculated with the Microsoft ExcelXlfit curve fitting software. For each compound, curves were generatedfrom percent inhibition calculated at 10 different concentrations byusing a four paramenter logistic model (model 205). The EC₅₀ data forthe compounds is shown in Table 2. Table 1 is the key for the data inTable 2.

[0398] Results TABLE 1 Biological Data Key for EC₅₀s Compounds* withCompounds with Compounds with EC₅₀s > 5 μM EC₅₀s > 1 μM but < 5 μM EC₅₀< 1 μM Group C Group B Group A

[0399] In Table 2, X_(W), X_(Z), and X_(S) indicate the points ofattachment for groups Z, W and A in Compounds I. For example in tableentry 1, for group Z, the point of attachment to group W is indicated ingroup Z as “X_(W)”; for group W, the point of attachment to group Z is“X_(Z)” and the point of attachment to S is “X_(S)”. TABLE 2 Examples(I)

Table Entry EC₅₀ (Example Group from Number.) Z W A Table 1  1 (Example1)

A  2 (Example 2)

B  3 (Example 3)

C  4 (Example 4)

C  5 (Example 5)

C  6 (Example 6)

C  7 (Example 7)

B  8 (Example 8)

B  9 (Example 9)

B 10 (Example 10)

C 11 (Example 11)

B 12 (Example 12)

A 12 (Example 13)

A 14 (Example 14)

C

[0400] The compounds of the present invention may be administeredorally, parenterally (including subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques), byinhalation spray, or rectally, in dosage unit formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand diluents.

[0401] Thus, in accordance with the present invention, there is furtherprovided a method of treating and a pharmaceutical composition fortreating viral infections such as HIV infection and AIDS. The treatmentinvolves administering to a patient in need of such treatment apharmaceutical composition comprising a pharmaceutical carrier and atherapeutically effective amount of a compound of the present invention.

[0402] The pharmaceutical composition may be in the form of orallyadministrable suspensions or tablets; nasal sprays, sterile injectablepreparations, for example, as sterile injectable aqueous or oleagenoussuspensions or suppositories.

[0403] When administered orally as a suspension, these compositions areprepared according to techniques well known in the art of pharmaceuticalformulation and may contain microcrystalline cellulose for impartingbulk, alginic acid or sodium alginate as a suspending agent,methylcellulose as a viscosity enhancer, and sweetners/flavoring agentsknown in the art. As immediate release tablets, these compositions maycontain microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and lactose and/or other excipients, binders,extenders, disintegrants, diluents, and lubricants known in the art.

[0404] The injectable solutions or suspensions may be formulatedaccording to known art, using suitable non-toxic, parenterallyacceptable diluents or solvents, such as mannitol, 1,3-butanediol,water, Ringer's solution or isotonic sodium chloride solution, orsuitable dispersing or wetting and suspending agents, such as sterile,bland, fixed oils, including synthetic mono- or diglycerides, and fattyacids, including oleic acid.

[0405] The compounds of this invention can be administered orally tohumans in a dosage range of 1 to 100 mg/kg body weight in divided doses.One preferred dosage range is 1 to 10 mg/kg body weight orally individed doses. Another preferred dosage range is 1 to 20 mg/kg bodyweight in divided doses. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

What is claimed is:
 1. A compound of Formula I, includingpharmaceutically acceptable salts thereof,

wherein: Z is

Q is selected from the group consisting of:

—W— is

R¹, R², R³, R⁴, and R⁵, are independently selected from the groupconsisting of hydrogen, halogen, cyano, nitro, COOR⁸, XR⁹ and B; R¹⁵,R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently H or(C₁₋₆)alkyl; wherein (C₁₋₆)alkyl is optionally substituted with one tothree same or different members selected from the group consisting ofhalogen, amino, OH, CN and NO₂; m is 1 or 2; R⁶ is O or does not exist;R⁷ is (CH₂)_(n)R¹⁰ , SO₂NH₂, SO₂NHMe or SO₂NMe₂; n is 0-6; R¹⁰ isselected from the group consisting of H, (C₁₋₆)alkyl, —C(O)—(C₁₋₆)alkyl,C(O)-phenyl and CONR¹¹R¹²; R¹¹ and R¹² are each independently H,(C₁₋₆)alkyl or phenyl; —represents a carbon-carbon bond or does notexist; A is NR¹³R¹⁴; R¹³ and R¹⁴ are independently selected from thegroup consisting of hydrogen, (C₁₋₆)alkyl, (C₁₋₆)alkenyl, (C₁₋₆)alkynyl,(C₁₋₆)alkoxy, (C₁₋₆)cycloalkyl, phenyl, and heteroaryl; wherein said(C₁₋₆)alkyl, phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from F; or R¹³ and R¹⁴taken together with the nitrogen atom to which they are attached forms aheteroalicyclic ring containing 3 to 6 atoms; heteroalicyclic isselected from the group consisting of azetidinyl, piperidinyl,piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,tetrahydrofuranyl and tetrahydropyranyl; heteroaryl is selected from thegroup consisting of pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,furanyl, thienyl, benzothienyl, thiazolyl, isothiazolyl, oxazolyl,benzooxazolyl, isoxazolyl, imidazolyl, benzoimidazolyl,1H-imidazo[4,5-b]pyridin-2-yl, 1H-imidazo[4,5-c]pyridin-2-yl,oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, tetrazinyl, triazinyland triazolyl; B is selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, C(O)NR²³R²⁴, phenyl and heteroaryl; wherein said(C₁₋₆)alkyl, phenyl and heteroaryl are independently optionallysubstituted with one to three same or different halogens or from one tothree same or different substituents selected from F; F is selected fromthe group consisting of (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl cyano, phenyl,heteroaryl, heteroalicyclic, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,—NR²⁵C(O)—(C₁₋₆)alkyl, —NR²⁶R²⁷, morpholino, nitro, —S(C₁₋₆)alkyl, -SPh,NR²⁵S(O)₂₋R²⁶, piperazinyl, N-Me piperazinyl, C(O)H, (CH2)_(n)COOR²⁸ and—CONR²⁹R³⁰; wherein said (C₁₋₆)alkyl, heteroaryl, or phenyl isoptionally substituted with one to three same or different halogens orone to three methyl groups; heteroaryl is selected from the groupconsisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl,isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl,tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, andpyrimidinyl; heteroalicyclic is selected from the group consisting ofaziridinyl, azetidinyl, pyrrolidinyl, piperazinyl, N-methyl piperazinyl,piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, azepinyl andmorpholinyl; R⁸, R⁹ and R²⁸ are independently selected from the groupconsisting of hydrogen and (C₁₋₆)alkyl; X is selected from the groupconsisting of NR³¹, O and S; R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁹, R³⁰, R³¹ areindependently selected from the group consisting of hydrogen,(C₁₋₆)alkyl, (C₁₋₆)alkoxy, phenyl and heteroaryl; wherein said(C₁₋₆)alkyl, phenyl, and heteroaryl are independently optionallysubstituted with one to three same or different group J; heteroaryl isselected from the group consisting of furanyl, thienyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl,pyridazinyl, and pyrimidinyl; J is selected from the group consisting of(C₁₋₆)alkyl, hydroxy, (C₁₋₆)alkoxy, halogen, benzyl,—NR³²C(O)—(C₁₋₆)alkyl, —NR³²R³³, —S(C₁₋₆)alkyl, -SPh, (CH2)_(n)COOR²⁸and —CONR³²R³³; wherein said (C₁₋₆)alkyl is optionally substituted withone to three same or different halogens; and R³² and R³³ areindependently selected from the group consisting of hydrogen and(C₁₋₆)alkyl; wherein said (C₁₋₆)alkyl is optionally substituted with oneto three same or different halogen, methyl, or CF₃ groups.
 2. A compoundof claim 1 wherein: Z is

R¹ is hydrogen; —represents a carbon-carbon bond; and R⁶ does not exist.3. A compound of claim 2 wherein: R⁷ is hydrogen; and R¹⁵, R¹⁶, R¹⁷,R¹⁸, R¹⁹, R²⁰, R²¹, R²² are each independently H or methyl with theproviso that a maximum of one of R¹⁵-R²² is methyl.
 4. A compound ofclaim 3 wherein: Q is a member selected from groups (A) and (B)consisting of:

provided R² and R³ are each independently hydrogen, methoxy or halogen;and

provided R² is hydrogen, methoxy or halogen.
 5. A compound of claim 4wherein: Q is a member selected from groups (A), (B) and (C) consistingof:

provided R is hydrogen, methoxy or halogen; R³is hydrogen;

provided R² and R³ are hydrogen; and

provided R² is hydrogen, methoxy or halogen; and R³ and R⁴ are hydrogen.6. A compound of claim 4 wherein: Q is

provided R² is hydrogen, methoxy or halogen; and R³is hydrogen.
 7. Acompound of claim 4 wherein: Q is

and R² and R³ are hydrogen.
 8. A compound of claim 4 wherein: Q is

R² is hydrogen, methoxy or halogen; and R³ and R⁴ are hydrogen.
 9. Acompound of claim 4 wherein: Q is:

R² is hydrogen, methoxy or halogen; and R³ and R⁴ are hydrogen.
 10. Acompound of claims 3, 5, 6, 7 or 9 wherein: B is selected from the groupconsisting of —C(O)NR²³R²⁴, phenyl and heteroaryl; wherein said phenylor heteroaryl is optionally substituted with one to three same ordifferent halogens or from one to two same or different substituentsselected from the group F.
 11. A compound of claims 3, 5 or 6 wherein: Ais selected from the group consisting of —NH(C₁-C₆alkyl),—N(C₁-C₆alkyl)₂, -NHfuryl, -NHPh, morpholinyl, N-Me piperazinyl,—N(—CH₂—)₃, —N(—CH₂—)₄, —N(—CH₂—)₅, and pyrazolyl.
 12. A compound ofclaim 5 wherein: A is selected from the group consisting of—NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -NHfuryl, -NHPh, morpholinyl, N-Mepiperazinyl, —N(—CH₂—)₃, —N(—CH₂—)₄, —N(—CH₂—)₅, and pyrazolyl; and B is—C(O)NHMe or —C(O)NH-heteroaryl; wherein said heteroaryl is optionallysubstituted with one to two substituents selected from the groupconsisting of halogen, (C₁-C₆ alkyl), amino, —NHC(O)—(C₁-C₆ alkyl),-methoxy, —COOH, —CH₂COOH, —CH₂CH₂COOH, —NH(C₁-C₆ alkyl) and —N(C₁-C₆alkyl)₂.
 13. A compound of claim 5 wherein: A is selected from the groupconsisting of —NH(C₁-C₆alkyl), —N(C₁-C₆alkyl)₂, -NHfuryl, -NHPh,morpholinyl, N-Me piperazinyl, —N(—CH₂—)₃, —N(—CH₂—)₄, —N(—CH₂—)₅, andpyrazolyl; and B is -triazolyl or pyrazolyl which is optionallysubstituted with one to two substituents selected from the groupconsisting of halogen, (C₁-C₆ alkyl), amino, —NHC(O)—(C₁-C₆ alkyl),-methoxy, —COOH, —CH₂COOH, —CH₂CH₂COOH, —NH(C₁-C₆ alkyl) and —N(C₁-C₆alkyl)₂.
 14. A compound selected from Examples 1-14.
 15. Apharmaceutical formulation which comprises an antiviral effective amountof a compound of Formula I, including pharmaceutically acceptable saltsthereof, as claimed in claim 1, and a pharmaceutically acceptablecarrier; wherein said formulation optionally contains an antiviraleffective amount of an AIDS treatment agent selected from the groupconsisting of: (a) an AIDS antiviral agent; (b) an anti-infective agent;(c) an immunomodulator; and (d) HIV entry inhibitors.
 16. A method fortreating mammals infected with the HIV virus, comprising administeringto said mammal an antiviral effective amount of a compound of Formula I,including pharmaceutically acceptable salts thereof, as claimed in claim1; optionally in combination with an antiviral effective amount of anAIDS treatment agent selected from the group consisting of: an AIDSantiviral agent, an anti-infective agent, an immunomodulator and HIVentry inhibitors.